transforming-growth-factor-beta and Hypertension

Curcumin, belongs to the curcuminoid family, is a natural phenolic compound, presenting low bioavailability and pleiotropic activity. Since ancient times, curcumin has been in use as food spices and folk remedy to treat cough, cold, cuts and wounds, and skin diseases. Preclinical and clinical studies have indicated that curcumin acts a promising therapeutic agent in the management of a wide array of health issues, viz., hyperlipidemia, metabolic syndrome, anxiety, arthritis, cancer and inflammatory diseases. Owing to its enormous potential, recent research has been focused on the synthesis of curcumin and its analogues for the management of metabolic disorders. In the current scenario, hypertension is considered as a key risk factor due to its involvement in various pathogeneses. Mechanistically, curcumin and its analogues like hexahydrocurcumin, tetrahydrocurcumin, etc. have been reported to elicit anti-hypertensive effect through diverse signalling pathways, viz., pathway mediated by Nrf2-ARE, NF-kB, NO/cGMP/PDE5/MMPs, RAAS/ACE, HAT/HDAC, G0/G1/apoptosis, CYP3A4, UCP2/PARP, VEGF/STAT/AXL/tyrosine kinase and TGF-β/Smad-mediated pathways. Thus, the present review has been aimed to highlight different molecular pathways involved in the amelioration of hypertension and associated conditions.

Topics: Antihypertensive Agents; Curcumin; Cytochrome P-450 CYP3A; Humans; Hypertension; NF-E2-Related Factor 2; NF-kappa B; Poly(ADP-ribose) Polymerase Inhibitors; Protein-Tyrosine Kinases; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

The most effective way to control severity and mortality rate of the novel coronavirus disease (COVID-19) is through sensitive diagnostic approaches and an appropriate treatment protocol. We aimed to identify the effect of adding corticosteroid and Tocilizumab to a standard treatment protocol in treating COVID-19 patients with chronic disease through hematological and lab biomarkers.. This study was performed retrospectively on 68 COVID-19 patients with chronic disease who were treated by different therapeutic protocols. The patients were categorized into four groups: control group represented the patients' lab results at admission before treatment protocols were applied; group 1 included patients treated with anticoagulants, Hydroxychloroquine, and antibiotics; group 2 comprised patients treated with Dexamethasone; and group 3 included patients treated with Dexamethasone and Tocilizumab.. The study paves the way into the effectiveness of combining Dexamethasone with Tocilizumab in treatment COVID-19 patients with chronic diseases.. La forma más eficaz de controlar la gravedad y la tasa de mortalidad de la enfermedad del nuevo coronavirus (COVID-19) es mediante enfoques de diagnóstico sensibles y un protocolo de tratamiento adecuado. Nuestro objetivo fue identificar el efecto de agregar corticosteroides y tocilizumab a un protocolo de tratamiento estándar en el tratamiento de pacientes con COVID-19 con enfermedad crónica a través de biomarcadores hematológicos y de laboratorio.. Este estudio se realizó de forma retrospectiva en 68 pacientes COVID-19 con enfermedad crónica que fueron tratados por diferentes protocolos terapéuticos. Los pacientes se clasificaron en cuatro grupos: el grupo de control representaba los resultados de laboratorio de los pacientes en el momento de la admisión antes de que se aplicaran los protocolos de tratamiento; el grupo 1 incluyó a pacientes tratados con anticoagulantes, hidroxicloroquina y antibióticos; el grupo 2 estaba compuesto por pacientes tratados con dexametasona; y el grupo 3 incluyó a pacientes tratados con dexametasona y tocilizumab.. El estudio allana el camino hacia la eficacia de la combinación de dexametasona con tocilizumab en el tratamiento de pacientes con COVID-19 con enfermedades crónicas.. The Child-Mother Index constitutes a potential useful risk factor indicator for statistical analyses on data after birth. The value of the Child-Mother Index based on the estimated fetal weight before birth deserves evaluation.. Six ceria supports synthesized by various synthesis methodologies were used to deposit cobalt oxide. The catalysts were thoroughly characterized, and their catalytic activity for complete methane oxidation was studied. The supports synthesized by direct calcination and precipitation with ammonia exhibited the best textural and structural properties as well as the highest degree of oxidation. The remaining supports presented poorer textural properties to be employed as catalytic supports. The cobalt deposited over the first two supports presented a good dispersion at the external surface, which induced a significant redox effect that increased the number of Co. Some studies show that children with obesity are more likely to receive a diagnosis of depression, anxiety, or attention-deficit hyperactivity disorder (ADHD). But this does not necessarily mean obesity causes these conditions. Depression, anxiety, or ADHD could cause obesity. A child's environment, including family income or their parents' mental health, could also affect a child's weight and mental health. Understanding the nature of these relationships could help scientists develop better interventions for both obesity and mental health conditions. Genetic studies may help scientists better understand the role of the environment in these conditions, but it's important to consider both the child's and their parents’ genetics in these analyses. This is because parents and children share not only genes, but also environmental conditions. For example, families that carry genetic variants associated with higher body weight might also have lower incomes, if parents have been affected by biases against heavier people in society and the workplace. Children in these families could have worse mental health because of effects of their parent’s weight, rather than their own weight. Looking at both child and adult genetics can help disentangle these processes. Hughes et al. show that a child's own body mass index, a ratio of weight and height, is not strongly associated with the child’s mental health symptoms. They analysed genetic, weight, and health survey data from about 41,000 8-year-old children and their parents. The results suggest that a child's own BMI does not have a large effect on their anxiety symptoms. There was also no clear evidence that a child's BMI affected their symptoms of depression or ADHD. These results contradict previous studies, which did not account for parental genetics. Hughes et al. suggest that, at least for eight-year-olds, factors linked with adult weight and which differ between families may be more critical to a child's mental health than a child’s own weight. For older children and adolescents, this may not be the case, and the individual’s own weight may be more important. As a result, policies designed to reduce obesity in mid-childhood are unlikely to greatly improve the mental health of children. On the other hand, policies targeting the environmental or societal factors contributing to higher body weights, bias against people with higher weights, and poor child mental health directly may be more beneficial.. The development of an efficient photocatalyst for C2 product formation from CO. Оценка антиастенического эффекта последовательной терапии левокарнитином (ЛК) и ацетилкарнитином (АЛК) пациентов с артериальной гипертензией и/или ишемической болезнью сердца (ИБС) с астеническим синдромом (АС).. В открытое сравнительное исследование были включены 120 пациентов в возрасте 54—67 лет с артериальной гипертензией и/или ИБС с АС. Пациенты 1-й группы (. У больных 1-й группы отмечено статистически значимое уменьшение различных проявлений АС. Отличия носили достоверный характер по сравнению как с исходным уровнем, так и со 2-й группой. Установлено эндотелийпротективное действие ЛК и АЛК.. Полученные результаты свидетельствуют, что у таких коморбидных пациентов использование ЛК и АЛК уменьшает выраженность проявлений АС, а установленные эндотелиотропные свойства препаратов позволяют рекомендовать их в составе комплексной персонифицированной терапии пациентов с сердечно-сосудистыми заболеваниями.. Naproxen sodium 440 mg/diphenhydramine 50 mg combination demonstrated improvement in sleep maintenance (WASO) vs. naproxen sodium 550 mg and higher efficiency in average daily pain reduction compared with the comparison groups. The treatment was well tolerated There were no serious or unexpected adverse events reported in the study.. Сравнительный анализ эффективности и безопасности новой комбинации напроксена натрия и дифенгидрамина у пациентов с неспецифическим болевым синдромом в пояснично-крестцовом отделе спины (M54.5 «Боль внизу спины») и нарушением сна (G47.0 «Нарушения засыпания и поддержания сна [бессонница]»).. Проведено проспективное многоцентровое рандомизированное открытое сравнительное в параллельных группах клиническое исследование. Пациенты были рандомизированы в 3 группы. Больные 1-й группы получали напроксен натрия (440 мг) и дифенгидрамин (50 мг), 2-й — напроксен натрия (550 мг), 3-й — парацетамол (1000 мг) и дифенгидрамин (50 мг). Исследуемые препараты пациенты принимали однократно перед сном в течение 3 дней. Все пациенты также принимали 275 мг (1 таблетка) напроксена натрия в качестве препарата фоновой терапии. Первичным критерием эффективности было общее время бодрствования после наступления сна (WASO), измеряемое методом актиграфии. Также использовались критерии оценки продолжительности и качества сна и выраженности боли.. Анализ эффективности проведен для ITT популяции (. Применение комбинации напроксена натрия (440 мг) и дифенгидрамина (50 мг) характеризовалось более выраженным поддержанием сна по сравнению с напроксеном натрия 550 мг и более высокой эффективностью в отношении снижения интенсивности боли по сравнению со 2-й и 3-й группами. Отмечена хорошая переносимость препарата, серьезных нежелательных явлений зарегистрировано не было.

Topics: Acetaminophen; Acetylcarnitine; Acetylcholinesterase; Acids; Acinetobacter baumannii; Acinetobacter Infections; Adaptation, Psychological; Adolescent; Adsorption; Adult; Aged; Alcohol Drinking; Alzheimer Disease; Amikacin; Ammonia; Anaerobiosis; Animals; Anorexia; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Anxiety; Aptamers, Nucleotide; Asthenia; Attention Deficit Disorder with Hyperactivity; Bacterial Proteins; Beryllium; beta-Lactamases; Biofuels; Biomass; Biosensing Techniques; Bismuth; Blister; Body Mass Index; Body Surface Area; Boronic Acids; Brain; Breast Neoplasms; Butyrylcholinesterase; Cannabis; Carbapenems; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Carboxylic Acids; Carcinoma, Hepatocellular; Cardiovascular Diseases; Carnitine; Case-Control Studies; Catalysis; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Child; China; Cholinesterase Inhibitors; Clarithromycin; Clostridioides; Clostridioides difficile; Clostridium Infections; Cohort Studies; Colistin; Colitis; Colon; Coloring Agents; Coronary Artery Bypass; Creatinine; Crystalloid Solutions; Cytokines; Depression; Dextran Sulfate; Dextrans; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Diarrhea; Dietary Supplements; Diphenhydramine; Disease Models, Animal; Disease Outbreaks; Double-Blind Method; Doxorubicin; Drosophila; Drug Tapering; Dysbiosis; Electrons; Escherichia coli; Extracellular Vesicles; Fatigue; Female; Fermentation; gamma-Cyclodextrins; Gastrointestinal Microbiome; Glucose; Graft Survival; Graft vs Host Disease; Head and Neck Neoplasms; Heart Arrest, Induced; Hematopoietic Stem Cell Transplantation; High-Intensity Interval Training; Hippocampus; Humans; Hydrogen-Ion Concentration; Hypertension; Incidence; Interferon-gamma; Italy; Kinetics; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Lactoferrin; Larva; Length of Stay; Lignin; Liver; Liver Neoplasms; Liver Transplantation; Living Donors; Low Back Pain; Lung; Lung Volume Measurements; Macrophages; Male; Melphalan; Men; Mendelian Randomization Analysis; Meropenem; Methane; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mitochondrial Proteins; Molecular Docking Simulation; Molecular Structure; Mothers; Motivation; Mycoplasma; Mycoplasma hominis; Mycoplasma Infections; NAD; Nanocomposites; Nanoparticles; Nanotubes, Carbon; Naproxen; Neovascularization, Pathologic; Neurons; Nitrates; Nucleolin; Opuntia; Paratyphoid Fever; Phenotype; Phosphatidylinositol 3-Kinases; Phytochemicals; Plant Extracts; Pregnancy; Prevalence; Prospective Studies; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Resveratrol; Retrospective Studies; Rifampin; Risk Factors; RNA, Messenger; Selenium; Sleep; Social Behavior; Soil; Soil Pollutants; Squamous Cell Carcinoma of Head and Neck; Staphylococcus aureus; Structure-Activity Relationship; Suicidal Ideation; Suicide; Superoxide Dismutase-1; Surveys and Questionnaires; Swimming; Syndrome; Tannins; Temperature; Transforming Growth Factor beta; Transplantation Conditioning; Treatment Outcome; Triple Negative Breast Neoplasms; Troponin T; Tumor Microenvironment; United Kingdom; Ureaplasma; Ureaplasma urealyticum; Urinary Tract Infections; Viscum; Waste Disposal Facilities; Wastewater; Water; Water Pollutants, Chemical; Wolfiporia; Young Adult

Extracellular matrix (ECM) is the foundation on which all cells and organs converge to orchestrate normal physiological functions. In the setting of pathology, the ECM is modified to incorporate additional roles, with modifications including turnover of existing ECM and deposition of new ECM. The fibroblast is center stage in coordinating both normal tissue homeostasis and response to disease. Understanding how fibroblasts work under normal conditions and are activated in response to injury or stress will provide mechanistic insight that triggers discovery of new therapeutic treatments for a wide range of disease. We highlight here fibroblast roles in the cancer, lung, and heart as example systems where fibroblasts are major contributors to homeostasis and pathology.

Topics: Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Gene Expression Regulation; Homeostasis; Humans; Hypertension; Inflammation; Lung; Myocardial Infarction; Myocardium; Neoplasms; Stromal Cells; Transforming Growth Factor beta; Wnt Signaling Pathway

This review includes a comprehensive, but succinct, summary on the essentials of TGF- β structure, family members, receptors, and intracellular mediators. Also provided is a select list of original publications that report novel roles and facets of TGF-β in vascular function and signaling in the contexts of health and disease.

Topics: Animals; Blood Pressure; Fibrosis; Humans; Hypertension; Neovascularization, Physiologic; Signal Transduction; Transforming Growth Factor beta

Elastin microfibril interface-located protein 1 (EMILIN1), a glycoprotein, is associated with elastin in the extracellular matrix (ECM) of arteries, lymph vasculature, and other tissues. EMILIN1 particularly has a niche role in elastin fiber biogenesis (elastogenesis) by aiding with the fusion of elastin fibers, rendering them more ordered. In addition to elastogenesis, EMILIN1 has been shown to have roles in maintenance of vascular cell morphology, smooth muscle cell adhesion to elastic fibers, and transforming growth factor (TGFβ) regulation, by inhibiting TGFβ activation via blocking the proteolytic production of the latency-associated peptide/active TGFβ complex. The increased TGFβ signaling induced during EMILIN1 deficiency alters TGFβ activity, resulting in vascular smooth muscle cell growth and vascular remodeling. The increasing systemic blood pressure associated with TGFβ signaling may be closely linked to the activity of other mediators that affect cardiovascular homeostasis, such as angiotensin II. The increase in prevalence of hypertension and other cardiovascular diseases in other disease states likely involve a complex activation of TGFβ signaling and ECM dysfunction. Thus, the interaction of TGFβ and ECM components appears to be integrative involving both structural alterations to vessels through EMILIN1 and changes in TGFβ signaling processes. This review summarizes the current knowledge on the EMILIN1-TGFβ relationship; the specific roles of EMILIN1 and TGFβ in blood pressure regulation, their synergistic interaction, and in particular the role of TGFβ (in conjunction with ECM proteins) in other disease states altering cardiovascular homeostasis.

Topics: Blood Pressure; Blood Vessels; Extracellular Matrix; Heart Diseases; Humans; Hypertension; Membrane Glycoproteins; Myocytes, Smooth Muscle; Peptides; Polymorphism, Single Nucleotide; Protein Precursors; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1

Hypertension and hyperglycaemia are major risk factors that result in chronic kidney disease (CKD). Achievement of blood pressure goals, optimal control of blood glucose levels and the use of agents to block the renin-angiotensin-aldosterone system slow the progression of CKD. However, not all patients are benefited by these interventions and novel strategies to arrest or reverse the pathological processes inherent in CKD are needed. The therapeutic potential of targeting KCa3.1 in CKD will be discussed in this review.. Blockade of KCa3.1 ameliorates activation of renal fibroblasts in diabetic mice by inhibiting the transforming growth factor-β1/small mothers against decapentaplegic pathway. A concomitant reduction in nuclear factor-κB activation in human proximal tubular cells under diabetic conditions has been observed. Advanced glycosylated endproducts induce both protein expression and current density of KCa3.1, which, in turn, mediates migration and proliferation of vascular smooth muscle cells via Ca²⁺-dependent signalling pathways.. Studies have clearly demonstrated a causal role of chronic hyperglycaemia and hypertension in the development of CKD. However, a large proportion of patients develop end-stage kidney disease despite strict glycaemic control and the attainment of recommended blood pressure goals. Therefore, it is essential to identify and validate novel targets to reduce the development and progression of CKD. Recent findings demonstrate that genetic deletion or pharmacologic inhibition of KCa3.1 significantly reduces the development of diabetic nephropathy in animal models. However, the consequences of blockade of KCa3.1 in preventing and treating established diabetic nephropathy in humans warrants further study.

Topics: Cell Movement; Cell Proliferation; Diabetic Nephropathies; Fibroblasts; Glycation End Products, Advanced; Humans; Hypertension; Intermediate-Conductance Calcium-Activated Potassium Channels; Muscle, Smooth, Vascular; NF-kappa B; Renal Insufficiency, Chronic; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Investigation into the underlying mechanisms of salt sensitivity has made important advances in recent years. This review examines in particular the effects of sodium and potassium on vascular function.. Sodium chloride (salt) intake promotes cutaneous lymphangiogenesis mediated through tissue macrophages and directly alters endothelial cell function, promoting increased production of transforming growth factor-β (TGF-β) and nitric oxide. In the setting of endothelial dysfunction, such as occurs with aging, diminished nitric oxide production exacerbates the vascular effects of TGF-β, promoting decreased arterial compliance and hypertension. Dietary potassium intake may serve as an important countervailing influence on the effects of salt in the vasculature.. There is growing appreciation that, independently of alterations in blood pressure, dietary intake of sodium and potassium promotes functional changes in the vasculature and lymphatic system. These changes may protect against development of salt-sensitive hypertension. While salt sensitivity cannot be ascribed exclusively to these factors, perturbation of these processes promotes hypertension during high-salt intake. These studies add to the list of genetic and environmental factors that are associated with salt sensitivity, but in particular provide insight into adaptive mechanisms during high salt intake.

Topics: Animals; Humans; Hypertension; Immune System; Nitric Oxide; Potassium, Dietary; Sodium Chloride, Dietary; Transforming Growth Factor beta

One of the critical points in the pathogenesis of aortic aneurysms (AAs) is the disruption of the balance between vascular extracellular matrix (ECM) deposition and degradation. AAs are common features in some genetically determined diseases of the connective tissue, such as Marfan and Ehlers-Danlos. Acquired factors determining an enhanced inflammatory state of the arterial wall also play a key role. Previous studies have determined the role of tumor growth factor β (TGF-β); as a principal mediator of the pathogenesis of the alterations of the arterial wall homeostasis in AAs. The medical management of any AA is mainly focused on the use of pharmacological agents that reduce hemodynamic stress of the aortic wall, since hypertension is the major risk factor for the enlargement and rupture of the AAs. However, this is far from being a comprehensive pathophysiology-based therapeutic approach. Drugs potentially able to reduce the release of TGF-β may play a role in the pathogenesis of the AAs. They work by improving matrix repair, decreasing the proteolytic pattern and inhibition of angiotensin-converting enzyme (ACE) as well as preventing angiotensin II-induced angiotensin type-1 receptor (AT1R) activation. A new pathophysiology-based therapeutic approach, involving the mechanisms leading to the rupture of the AAs, could represent an additional tool in combination with the current established antihypertensive therapy.

Topics: Animals; Aortic Aneurysm; Atherosclerosis; Autoimmunity; Genetic Predisposition to Disease; Humans; Hypertension; Insulin Resistance; Metalloproteases; Oxidative Stress; Risk Factors; Transforming Growth Factor beta

Chymase plays a crucial role in angiotensin II formation in various tissues. Angiotensin II induces gene expressions of transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9, and chymase also converts precursors of TGF-β and MMP-9 to their active forms. All of angiotensin II, TGF-β and MMP-9 are considered to be closely involved in the development and progression of metabolic syndrome and its complications. In a diabetic animal model, chymase induced pancreatic disorganization via attack of oxidative stress induced by augmentation of chymase-forming angiotensin II. In atherosclerotic lesions in patients, accumulation of chymase-positive cells was observed, and chymase inhibition prevented the development of atherosclerosis in an animal model. In Apo E-deficient mice, chymase inhibition prevents the development of angiotensin II-induced abdominal aneurysmal aorta (AAA). In this model, the AAA development on an increase in MMP-9 activities induced by angiotensin II, but the inhibition of MMP-9 activation by chymase inhibitor resulted in attenuation of the AAA development. Cardiac dysfunction after myocardial infarction was also attenuated by chymase inhibition. Steatosis and fiblosis in liver were strongly prevented by chymase inhibition in an animal model with nonalcoholic steatohepatitis which is involved in metabolic syndrome. Therefore, chymase inhibition may be useful for attenuating MMP-9 and TGF-β levels, in addition to reducing angiotensin II formation, and this function may provide powerful preventions of organ damages. In this review, we propose the significance of chymase as a target to prevent complications of metabolic syndrome.

Topics: Angiotensin II; Animals; Atherosclerosis; Chymases; Diabetes Complications; Diabetic Retinopathy; Fatty Liver; Humans; Hypertension; Matrix Metalloproteinase 9; Metabolic Syndrome; Mice; Transforming Growth Factor beta

Topics: Cardiac Output; Endothelium, Vascular; Humans; Hypertension; Ion Channels; Mutation; Natriuretic Peptides; Nitric Oxide; Oxidative Stress; Renin-Angiotensin System; Sodium, Dietary; Sympathetic Nervous System; Transforming Growth Factor beta; Vascular Resistance

Diabetic nephropathy is characterized by excessive amassing of extracellular matrix (ECM) with thickening of glomerular and tubular basement membranes and increased amount of mesangial matrix, which ultimately progress to glomerulosclerosis and tubulo-interstitial fibrosis. In view of this outcome, it would mean that all the kidney cellular elements, i.e., glomerular endothelia, mesangial cells, podocytes, and tubular epithelia, are targets of hyperglycemic injury. Conceivably, high glucose activates various pathways via similar mechanisms in different cell types of the kidney except for minor exceptions that are related to the selective expression of a given molecule in a particular renal compartment. To begin with, there is an obligatory excessive channeling of glucose intermediaries into various metabolic pathways with generation of advanced glycation products (AGEs), activation of protein kinase C (PKC), increased expression of transforming growth factor-beta (TGF-beta), GTP-binding proteins, and generation of reactive oxygen species (ROS). The ROS seem to be the common denominator in various pathways and are central to the pathogenesis of hyperglycemic injury. In addition, there are marked alterations in intraglomerular hemodynamics, i.e., hyperfiltration, and this along with metabolic derangements adversely compounds the hyperglycemia-induced injury. Here, the information compiled under various subtitles of this article is derived from an enormous amount of data summarized in several excellent literature reviews, and thus their further reading is suggested to gain in-depth knowledge of each of the subject matter.

Topics: Cell Cycle Proteins; Diabetic Nephropathies; Disease Progression; Enzyme Activation; Glucose; Glycation End Products, Advanced; GTP-Binding Proteins; Hypertension; Kidney; Protein Kinase C; Reactive Oxygen Species; Signal Transduction; Transforming Growth Factor beta

Hypertensive nephrosclerosis is the second most common cause of end-stage renal disease, however morphologic evidence on the subject is poorly understood. A perennial and vexing problem in understanding kidney hypertension is that correlations between hypertension and vascular and glomerular lesions are only moderate, in part because all of these lesions are present to a greater or lesser degree in the normotensive, aging kidney, with racial differences in severity further compounding the problem. This review looks at newer data on this topic.. Recent data suggest that there are two different processes leading to glomerulosclerosis, and the combination of the two begins to explain why global correlations between hypertension and morphologic lesions are destined to remain poor. Arterial stiffening with increased pulse pressure down as far as the afferent arteriolar level likely plays an important role in the progression of glomerular lesions. Loss of renal autoregulation with glomerular hypertrophy, hyperfiltration, and focal segmental glomerulosclerosis is now recognized to contribute significantly to nephrosclerosis, particularly in the black population. Ischemic glomerulosclerosis, however, may ultimately be the most important lesion, with consequent hypoxia in the parenchyma beyond, leading to tubular atrophy and interstitial fibrosis.. Hypertensive nephrosclerosis should be seen as a process with two principal modes of glomerular sclerosis, ischemic and hypertrophic, with consequent focal segmental glomerulosclerosis, contributing variably to renal failure according to race and level of hypertension.

Topics: Animals; Atrophy; Blood Pressure; Cell Hypoxia; Disease Models, Animal; Elasticity; Fibrosis; Glomerular Filtration Rate; Homeostasis; Humans; Hypertension; Hypertrophy; Inflammation Mediators; Ischemia; Kidney Glomerulus; Nephrosclerosis; Renal Artery; Renal Circulation; Transforming Growth Factor beta

Chronic kidney diseases are emerging as a worldwide public health problem. The progression of kidney diseases closely correlates with the accumulation of extracellular matrix leading to glomerulosclerosis and tubulointerstitial injury. Transforming growth factor (TGF)-beta has been identified as a key mediator of kidney matrix accumulation. Overexpression of TGF-beta isoforms and their receptors was observed in a variety of renal diseases in both animals and humans. Given its crucial role in fibrotic kidney disease, TGF-beta has been recently considered as a possible target in the management of chronic renal diseases. This review discusses the role of TGF-beta in renal fibrosis and provides an overview of the strategies that, when interfering with TGF-beta expression and signalling, could be employed as new renoprotective treatments.

Topics: Animals; Disease Progression; Humans; Hypertension; Kidney Failure, Chronic; Signal Transduction; Transforming Growth Factor beta

One of the most frequent types of organ damage developing in the course of hypertension is left ventricular hypertrophy (LVH). The percentage of hypertensive patients with LVH, assessed with echocardiographic method, amounts to 20-60%, depending on blood pressure level and duration of hypertension. This review includes current opinions on the role of transforming growth factor Beta1 (TGFP31), basic fibroblast growth factor (bFGF, FGF2), and insulin-like growth factor-1 (IGF-1) in the development of LVH in the course of hypertension. TGFBeta1 is a cytokine involved in the regulation of proliferation and cell differentiation. Its action is mainly directed towards the connective tissue cells, which it stimulates into production of collagen I and III. Increased levels of TGFbeta1 have been found both in animal models and in patients with hypertension and LVH. Growth factors bFGF and IGF-1 activate cell proliferation and have anti-apoptotic action. The role of bFGF and IGF-1 has been demonstrated in animal models; however, results of observations in subjects with hypertension and LVH are inconsistent. Discussed growth factors and cytokines and cell signalling pathways related to them might in future appear as targets for therapeutic intervention.

Topics: Cytokines; Fibroblast Growth Factor 2; Humans; Hypertension; Hypertrophy, Left Ventricular; Insulin-Like Growth Factor I; Myocardium; Transforming Growth Factor beta

Among the GTP-binding proteins, Rho is known to function as a molecular switch in various cellular functions. Among the Rho effectors, the cellular function and signal transduction of Rho-kinase have been extensively studied. However, information about its in vivo functions is still limited. With the recent development of a specific Rho-kinase inhibitor such as Y-27632 and fasudil, the understanding of the role of the Rho/Rho-kinase pathway in vitro and in vivo has advanced. However, to date, there have been few studies investigating the role of Rho-kinase in renal disease. Recent studies have shown that Rho-kinase inhibitor significantly attenuated the tubulointerstitial fibrosis in kidney induced by unilateral ureteral obstruction. However, there have been few studies investigating the role of the Rho/Rho-kinase pathway in hypertensive glomerular sclerosis. In this review, we described the role of the Rho/Rho-kinase pathway in the progression of renal glomerulosclerosis in several forms of hypertensive rats. Our results suggest that chronic inhibition of the Rho-kinase pathway may be a new therapeutic approach for hypertensive glomerulosclerosis. Our results also suggest that the mechanism of the renoprotective effect of Rho-kinase inhibitor is partly mediated via inhibition of extracellular matrix gene expression, monocytes/macrophages infiltration, oxidative stress, and upregulation of eNOS gene expression.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Blood Pressure; Collagen; Disease Models, Animal; Fibrosis; Glomerulosclerosis, Focal Segmental; Hypertension; Intracellular Signaling Peptides and Proteins; Kidney; Nitric Oxide Synthase Type III; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Rats; rho GTP-Binding Proteins; rho-Associated Kinases; Signal Transduction; Transforming Growth Factor beta

Topics: Aldosterone; Amyloid beta-Protein Precursor; Animals; Benzamidines; Epithelial Sodium Channels; Guanidines; Humans; Hypertension; Immediate-Early Proteins; Membrane Glycoproteins; Protease Nexins; Protein Serine-Threonine Kinases; Receptors, Cell Surface; Serine Endopeptidases; Serine Proteinase Inhibitors; Sodium Channels; Transforming Growth Factor beta; Trypsin Inhibitor, Kunitz Soybean

Topics: Antihypertensive Agents; Biglycan; Cardiovascular Diseases; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Hypertension; Matrix Metalloproteinases; Proteoglycans; Renin-Angiotensin System; Transforming Growth Factor beta

Transforming growth factor beta-1 is involved in local signaling for a variety of human diseases including renal diseases, cardiac hypertrophy and fibrosis in heart failure, hepatic fibrosis, and pulmonary fibrosis. Elevated levels of circulating transforming growth factor beta-1 result in organ fibrosis in animal models. In humans smoking, hypertension, diabetes and obesity appear to result in elevated circulating levels. This paper outlines a hypothesis that elevated circulating levels of transforming growth factor beta-1 are part of the molecular link between several entities that have epidemiologic ties including hypertension, diabetes, smoking and obesity on one hand and diseases resulting in organ fibrosis on the other including renal disease and cardiac fibrosis and hypertrophy in heart failure. Additionally, it is suggested that elevated levels are not simply a marker of a similar mechanism of disease production but that elevated levels of circulating transforming growth factor beta-1 lead to disease production and to the synergy of risk factors seen in production of human fibrotic diseases.

Topics: Animals; Diabetes Mellitus; Fibrosis; Humans; Hypertension; Models, Animal; Obesity; Signal Transduction; Smoking; Transforming Growth Factor beta; Transforming Growth Factor beta1

Patients with uncontrolled essential hypertension have elevated concentrations of superoxide anion (O(2)(-*)), hydrogen peroxide (H(2)O(2)), lipid peroxides, endothelin, and transforming growth factor-beta (TGF-beta) with a simultaneous decrease in endothelial nitric oxide (eNO), superoxide dismutase (SOD), vitamin E, and long-chain polyunsaturated fatty acids (LCPUFAs). Physiological concentrations of angiotensin II activate NAD(P)H oxidase and trigger free radical generation (especially that of O(2)(-*)). Normally, angiotensin II-induced oxidative stress is abrogated by adequate production and release of eNO, which quenches O(2)(-*) to restore normotension. Angiotensin II also stimulates the production of endothelin and TGF-beta. TGF-beta enhances NO generation, which in turn suppresses TGF-beta production. Thus, NO has a regulatory role on TGF-beta production and is also a physiological antagonist of endothelin. Antihypertensive drugs suppress the production of O(2)(-*) and TGF-beta and enhance eNO synthesis to bring about their beneficial actions. LCPUFAs suppress angiotensin-converting enzyme (ACE) activity, reduce angiotensin II formation, enhance eNO generation, and suppress TGF-beta expression. Perinatal supplementation of LCPUFAs decreases insulin resistance and prevents the development of hypertension in adult life, whereas deficiency of LCPUFAs in the perinatal period results in raised blood pressure later in life. Patients with essential hypertension have low concentrations of various LCPUFAs in their plasma phospholipid fraction. Based on this, it is proposed that LCPUFAs serve as endogenous regulators of ACE activity, O(2)(-*), eNO generation, and TGF-beta expression. Further, LCPUFAs have actions similar to statins, inhibit (especially omega-3 fatty acids) cyclooxygenase activity and suppress the synthesis of proinflammatory cytokines, and activate the parasympathetic nervous system, all actions that reduce the risk of major vascular events. Hence, it is proposed that availability of adequate amounts of LCPUFAs during the critical periods of growth prevents the development of hypertension in adulthood.

Topics: Animals; Antihypertensive Agents; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Humans; Hypertension; Nitric Oxide; Peptidyl-Dipeptidase A; Superoxides; Transforming Growth Factor beta

In agreement with previous data in the literature, our results indicate that serotonin, a monoamine neurotransmitter, can also regulate cell proliferation, cell movements and cell differentiation. We have recently shown that serotonin is required for embryonic heart development. Genetic ablation of the 5-HT2B receptor leads to partial embryonic and postnatal lethality with abnormal heart development. Similar molecular mechanisms seem to be involved in adult cardiomyocytes since mutant mice surviving to adulthood display a dilated cardiomyopathy. Furthermore this receptor appears to be involved in survival of cardiomyocytes. The 5-HT2B receptor is also implicated in systemic hypertension. Furthermore, mice with pharmacological or genetic ablation of 5-HT2B receptor are totally resistant to hypoxia-induced pulmonary hypertension, indicating that this receptor is regulating the pathologic vascular proliferation leading to this disease. Underlying mechanisms are still to be discovered.

Topics: Adult; Animals; Cardiomyopathy, Dilated; Cell Survival; Fenfluramine; Fetal Heart; Genes, Lethal; Genetic Predisposition to Disease; Heart Defects, Congenital; Humans; Hypertension; Hypertension, Pulmonary; Hypoxia; Mice; Mice, Knockout; Mice, Transgenic; Muscle, Smooth, Vascular; Myocytes, Cardiac; Organ Specificity; Pancreatic Elastase; Pulmonary Artery; Rats; Receptor, Serotonin, 5-HT2B; Serotonin; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Angiotensin II; Animals; Apoptosis; Arteriosclerosis; Autocrine Communication; Down-Regulation; Endothelium, Vascular; Hepatocyte Growth Factor; Humans; Hypertension; Kidney Tubules; Paracrine Communication; Transforming Growth Factor beta

Topics: Angiotensin II; Animals; Cell Division; Collagen; Endothelin-1; Extracellular Matrix; Fibroblast Growth Factor 2; Fibroblasts; Glomerulosclerosis, Focal Segmental; Humans; Hypertension; Liver Cirrhosis; Myoblasts, Cardiac; Myocardial Infarction; Pulmonary Fibrosis; Receptors, Endothelin; Transforming Growth Factor beta; Ventricular Remodeling

Discordant findings are reported on the left ventricular transforming growth factor-beta(1) (TGF-beta(1)) mRNA levels in various rat models. Left ventricular TGF-beta(1) mRNA levels did not differ between spontaneously hypertensive rats (SHR) and normal rats, between deoxycorticosterone (DOCA)-salt and sham-operated hypertensive rats, but were increased in stroke-prone spontaneously hypertensive rats (SHRSP) and in post-myocardial infarction (MI) rats. Renal cortical TGF-beta(1) mRNA levels were, however, higher in DOCA-salt hypertensive rats. Angiotensin II subtype 1 receptor antagonism (AT(1)R) and angiotensin converting enzyme inhibition (ACEI) decreased left ventricular and vascular smooth muscle TGF-beta(1) mRNA levels in SHR and renal TGF-beta(1) mRNA in DOCA-salt hypertensive rats and in SHRSP. In post-MI rats ventricular TGF-beta(1) mRNA decreased by AT(1)R antagonism. In essential hypertensive patients, TGF-beta(1) protein as well as TGF-beta(1) mRNA levels are hyperexpressed. The TGF-beta(1) overproduction in hypertension can be attributed to various factors such as elevated angiotensin II, increased systemic blood pressure (BP) per se, increased fluid shear stress and a differential expression of TGF-beta(1) linked to DNA polymorphism in the promoter. The Arg(25) polymorphism in the TGF-beta(1) gene is associated with higher BP. A higher plasma TGF-beta(1) concentration is found in hypertensive patients with microalbuminuria and left ventricle hypertrophy. In these patients, AT(1)R antagonism and ACEI reduced these plasma TGF-beta(1) levels significantly.

Topics: Angiotensin II; Animals; Blood Pressure; Humans; Hypertension; Models, Animal; Rats; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Animals; Collagen; Fibrosis; Humans; Hypertension; Hypertrophy, Left Ventricular; ortho-Aminobenzoates; Rats; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Actin Cytoskeleton; Actins; Animals; Capillaries; Carrier Proteins; Cell Adhesion; Collagen; Diabetic Nephropathies; Elasticity; Elastin; Endothelium, Vascular; Fibrillins; Glomerular Mesangium; Glutathione; Humans; Hypertension; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Latent TGF-beta Binding Proteins; Mammals; Membrane Glycoproteins; Mice; Microfilament Proteins; Permeability; Rats; Transforming Growth Factor beta

Hypertension is associated with a number of adverse morphologic and functional changes in the cardiovascular system. These include remodeling of the left ventricle, alterations in the morphology and mechanical properties of the vasculature, and the development of endothelial dysfunction. Recent studies have shown that angiotensin II is capable of mediating these changes via its interaction with the angiotensin II type 1 receptor. These nonhemodynamic effects of angiotensin II are independent of its effect on blood pressure. Thus, elevated levels of angiotensin II may lead directly to many hypertension-associated pathologies. Recent evidence that mechanical strain, oxidized low-density lipoprotein cholesterol, and aldosterone can cause upregulation of angiotensin II type 1 receptors indicates that activation of the renin-angiotensin system is not necessary for the actions of angiotensin II to be amplified. Because the strain on the vessel wall may be increased under conditions of hypertension, increased arterial pressure may amplify the actions of angiotensin II without a discernible increase in plasma angiotensin II levels. In both the myocardium and the peripheral vasculature, fibrosis is a major component of the remodeling that occurs in hypertension. There is substantial evidence that transforming growth factor beta-1 (TGF-beta(1)) mediates angiotensin-II-induced fibrosis in patients with hypertension and in those with a variety of nephropathies. Mechanical strain also induces fibrosis in a mechanism mediated by TGF-beta(1). This cytokine thus represents a common pathway by which angiotensin II and increased arterial pressure may induce cardiovascular fibrosis.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovascular Diseases; Humans; Hypertension; Renin-Angiotensin System; Transforming Growth Factor beta

Hypertension is prevalent world-wide, and it affects over 50 million individuals in the United States alone. African Americans (blacks) have a high prevalence of hypertension, develop it at an earlier age, and suffer excessively from severe or malignant hypertension. They also have a high prevalence of target organ damage attributable to hypertension, including left ventricular hypertrophy, stroke, end-stage renal disease (ESRD) and coronary artery disease. Hypertensive nephrosclerosis is particularly more prevalent in blacks compared to whites, and there is evidence that factors in addition to elevated blood pressure contribute to its pathogenesis. Transforming growth factor-beta 1 (TGF-beta1) is a fibrogenic cytokine that has been implicated in the development and progression of experimental and human renal diseases. We have demonstrated that blacks with ESRD have higher circulating levels of TGF-beta1 protein compared to whites with ESRD. We have also found that hyperexpression of TGF-beta1 is more frequent in blacks with hypertension than in whites. We propose that TGF-beta1 hyperexpression may be an important mediator of hypertension and hypertensive nephrosclerosis. We hypothesize also that the increased frequency of TGF-beta1 hyperexpression may contribute to the excess burden of ESRD in blacks. Based on our hypotheses, and the observations that angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists reduce angiotensin II-mediated stimulation of TGF-beta1 production, we propose that treatment with these agents might be efficacious in preventing or slowing the progression of target organ damage in hypertensive blacks.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Black People; Coronary Disease; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Linear Models; Prevalence; Stroke; Transforming Growth Factor beta; White People

The normal myocardium is composed of a variety of cells: cardiac myocytes and noncardiomyocytes, which include endothelial and vascular smooth muscle cells and fibroblasts. Hypertensive heart disease involves a structural remodeling of muscular and nonmuscular compartments. It is not the quantity but rather the quality of myocardium that accounts for pathologic hypertrophy and predisposes to ventricular dysfunction and arrhythmias, which, in turn, confer increased risk of adverse cardiovascular events. Herein, factors regulating growth of these compartments are reviewed and in particular signals involved in promoting adverse remodeling of intramyocardial coronary arteries and arterioles by fibrous tissue.

Topics: Animals; Cardiomegaly; Cell Division; Coronary Vessels; Endomyocardial Fibrosis; Fibroblasts; Growth Inhibitors; Growth Substances; Humans; Hypertension; Models, Cardiovascular; Myocardium; Nitric Oxide; Renin-Angiotensin System; Transforming Growth Factor beta

The molecular mechanisms of the exaggerated growth of vascular smooth muscle cells (VSMC) in hypertension are reviewed based on our previous experimental data. Spontaneously hypertensive rats (SHR)-derived VSMC increasingly express angiotensinogen, cathepsin D and angiotensin-converting enzyme (ACE) mRNAs, compared to cells from normotensive Wistar-Kyoto (WKY) rats, indicating the presence of an Ang II generating system in a homogeneous culture of VSMC from SHR. The produced Ang II then induces TGF-beta. SHR-derived VSMC show the distinct expression and abnormal regulation by Ang II of TGF-beta receptors when compared with cells from WKY rats, which express TGF-beta type II receptor predominantly to induce PDGF A-chain stimulation of VSMC growth. These findings imply that the increased growth of VSMC in hypertension is a primary event independent of high blood pressure, and is associated with endogenous Ang II-related growth factors.

Topics: Animals; Cell Division; Cells, Cultured; Hypertension; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta

Topics: Animals; Cytokines; Extracellular Matrix Proteins; Glomerular Mesangium; Humans; Hypertension; Kidney Diseases; Kidney Glomerulus; Transforming Growth Factor beta

1. Transforming growth factors-beta (TGF-beta) are multifunctional proteins that regulate cell growth, differentiation, migration and extracellular matrix production and have an important role in embryonic development and tissue remodelling. 2. The diverse biological actions of TGF-beta are elicited following their interaction with type I and type II TGF-beta receptors, both of which are transmembrane serine/threonine kinases, suggesting an important role for protein phosphorylation in the mechanism of action of these cytokines on the growth of cells and their extracellular environment. 3. Alterations in TGF-beta gene expression and action in various cell types associated with the cardiovascular system may contribute to the pathophysiology of a number of diseases, such as hypertension, atherosclerosis and restenosis, as well as the development of cardiac abnormalities.

Topics: Animals; Arteriosclerosis; Cardiovascular System; ErbB Receptors; Heart Diseases; Humans; Hypertension; Receptors, Transforming Growth Factor beta; Second Messenger Systems; Transforming Growth Factor beta

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional cytokine capable of regulating the growth and differentiation of many cell types, as well as regulating their environment in the blood vessel wall. Its production by endothelium and/or vascular smooth muscle is stimulated by biophysical forces, growth factors and also vasoconstrictors. In hypertension TGF-beta 1 gene transcription is most likely elevated by a combination of physical and chemical stimuli with the cytokine acting to increase the production of extracellular matrix proteins or to modulate smooth muscle cellular growth, producing hypertrophy, polyploidy or proliferation. With respect to the latter, TGF-beta 1 potentiates the proliferative effects of many receptor tyrosine kinase-activating growth factors in vascular smooth muscle from SHR, but inhibits such proliferation in WKY smooth muscle. It also differentially affects collagen production by the two cell types. It is suggested that the augmented proliferative response in renal hypertensive SHR, compared to renal hypertensive WKY, is the consequence of these differential effects of TGF-beta 1 on smooth muscle cell proliferation. TGF-beta 1 is also likely to be a significant contributor to the development of vascular hypertrophy in genetic hypertension.

Topics: Animals; Blood Vessels; Endothelium, Vascular; Gene Expression Regulation; Hypertension; Hypertrophy; Muscle, Smooth, Vascular; Transforming Growth Factor beta

Faster growth is observed in cultured vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) compared to cells from normotensive Wistar Kyoto (WKY) rats. It has been reported that transforming growth factor-beta (TGF beta), a bifunctional growth factor, shows higher mRNA accumulation in VSMC from SHR. Antisense oligodeoxynucleotide (ODN) complementary to TGF beta 1 mRNA significantly suppressed DNA synthesis of VSMC from SHR at high cell density in a dose-dependent manner, but elicited little inhibition of VSMC from WKY rats. Antisense ODN resulted in a depression of the cell number increase in SHR VSMC only. While DNA synthesis of VSMC was inhibited by antisense ODN at high cell density, it was stimulated at low cell density in both strains. In the presence of antisense ODN, plasmin, an activator of TGF beta, was unable to stimulate DNA synthesis of VSMC. These findings implicate a role of endogenous TGF beta in the exaggerated growth of VSMC from SHR.

Topics: Animals; Base Sequence; Cell Division; Hypertension; Molecular Sequence Data; Muscle, Smooth, Vascular; Oligonucleotides, Antisense; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Transforming Growth Factor beta

The increased growth potential of vascular smooth muscle cells (VSMCs) represents one of the crucial anomalies responsible for the development of essential hypertension, diabetic macroangiopathy, and atherosclerosis. The exaggerated response to growth factors of VSMC from spontaneously hypertensive rats (SHRs) persists in culture when compared with normotensive Wistar-Kyoto control rats, indicating an intrinsic defect in the hypertension-producing mechanism. This greater proliferation is characterized by two intermediate phenotypes: (1) accelerated entry into the S phase of the cell cycle, which results from hyperresponsiveness to epidermal growth factor and platelet-derived growth factor, and (2) abnormal contact inhibition. The enhanced expression of transforming growth factor beta 1 (TGF-beta 1) messenger ribonucleic acid in SHRs precedes this altered contact inhibition, and only VSMCs from SHRs respond to exogenously added TGF-beta 1 at a high cell density, which suggests that abnormal TGF-beta 1 autoregulation may be implicated in the second phenotype. Platelets contain major growth factors for VSMC. Platelet extracts from hypertensive and diabetic patients present augmented growth-promoting activity on VSMCs, which is most evident when both diseases occur simultaneously. Growth-promoting activity may be further influenced by antihypertensive therapy. This growth-promoting activity is increased by hydrochlorothiazide but not by indapamide, atenolol, or captopril in diabetic hypertensive and nondiabetic hypertensive patients. In conclusion, VSMCs in hypertension manifest an intrinsic growth defect that is modulated by extrinsic platelet growth factors and antihypertensive drugs.

Topics: Animals; Antihypertensive Agents; Cell Division; Cells, Cultured; Gene Expression Regulation; Growth Substances; Humans; Hypertension; Muscle, Smooth, Vascular; Phenotype; Rats; Rats, Inbred SHR; Transforming Growth Factor beta

The most effective way to control severity and mortality rate of the novel coronavirus disease (COVID-19) is through sensitive diagnostic approaches and an appropriate treatment protocol. We aimed to identify the effect of adding corticosteroid and Tocilizumab to a standard treatment protocol in treating COVID-19 patients with chronic disease through hematological and lab biomarkers.. This study was performed retrospectively on 68 COVID-19 patients with chronic disease who were treated by different therapeutic protocols. The patients were categorized into four groups: control group represented the patients' lab results at admission before treatment protocols were applied; group 1 included patients treated with anticoagulants, Hydroxychloroquine, and antibiotics; group 2 comprised patients treated with Dexamethasone; and group 3 included patients treated with Dexamethasone and Tocilizumab.. The study paves the way into the effectiveness of combining Dexamethasone with Tocilizumab in treatment COVID-19 patients with chronic diseases.. La forma más eficaz de controlar la gravedad y la tasa de mortalidad de la enfermedad del nuevo coronavirus (COVID-19) es mediante enfoques de diagnóstico sensibles y un protocolo de tratamiento adecuado. Nuestro objetivo fue identificar el efecto de agregar corticosteroides y tocilizumab a un protocolo de tratamiento estándar en el tratamiento de pacientes con COVID-19 con enfermedad crónica a través de biomarcadores hematológicos y de laboratorio.. Este estudio se realizó de forma retrospectiva en 68 pacientes COVID-19 con enfermedad crónica que fueron tratados por diferentes protocolos terapéuticos. Los pacientes se clasificaron en cuatro grupos: el grupo de control representaba los resultados de laboratorio de los pacientes en el momento de la admisión antes de que se aplicaran los protocolos de tratamiento; el grupo 1 incluyó a pacientes tratados con anticoagulantes, hidroxicloroquina y antibióticos; el grupo 2 estaba compuesto por pacientes tratados con dexametasona; y el grupo 3 incluyó a pacientes tratados con dexametasona y tocilizumab.. El estudio allana el camino hacia la eficacia de la combinación de dexametasona con tocilizumab en el tratamiento de pacientes con COVID-19 con enfermedades crónicas.. The Child-Mother Index constitutes a potential useful risk factor indicator for statistical analyses on data after birth. The value of the Child-Mother Index based on the estimated fetal weight before birth deserves evaluation.. Six ceria supports synthesized by various synthesis methodologies were used to deposit cobalt oxide. The catalysts were thoroughly characterized, and their catalytic activity for complete methane oxidation was studied. The supports synthesized by direct calcination and precipitation with ammonia exhibited the best textural and structural properties as well as the highest degree of oxidation. The remaining supports presented poorer textural properties to be employed as catalytic supports. The cobalt deposited over the first two supports presented a good dispersion at the external surface, which induced a significant redox effect that increased the number of Co. Some studies show that children with obesity are more likely to receive a diagnosis of depression, anxiety, or attention-deficit hyperactivity disorder (ADHD). But this does not necessarily mean obesity causes these conditions. Depression, anxiety, or ADHD could cause obesity. A child's environment, including family income or their parents' mental health, could also affect a child's weight and mental health. Understanding the nature of these relationships could help scientists develop better interventions for both obesity and mental health conditions. Genetic studies may help scientists better understand the role of the environment in these conditions, but it's important to consider both the child's and their parents’ genetics in these analyses. This is because parents and children share not only genes, but also environmental conditions. For example, families that carry genetic variants associated with higher body weight might also have lower incomes, if parents have been affected by biases against heavier people in society and the workplace. Children in these families could have worse mental health because of effects of their parent’s weight, rather than their own weight. Looking at both child and adult genetics can help disentangle these processes. Hughes et al. show that a child's own body mass index, a ratio of weight and height, is not strongly associated with the child’s mental health symptoms. They analysed genetic, weight, and health survey data from about 41,000 8-year-old children and their parents. The results suggest that a child's own BMI does not have a large effect on their anxiety symptoms. There was also no clear evidence that a child's BMI affected their symptoms of depression or ADHD. These results contradict previous studies, which did not account for parental genetics. Hughes et al. suggest that, at least for eight-year-olds, factors linked with adult weight and which differ between families may be more critical to a child's mental health than a child’s own weight. For older children and adolescents, this may not be the case, and the individual’s own weight may be more important. As a result, policies designed to reduce obesity in mid-childhood are unlikely to greatly improve the mental health of children. On the other hand, policies targeting the environmental or societal factors contributing to higher body weights, bias against people with higher weights, and poor child mental health directly may be more beneficial.. The development of an efficient photocatalyst for C2 product formation from CO. Оценка антиастенического эффекта последовательной терапии левокарнитином (ЛК) и ацетилкарнитином (АЛК) пациентов с артериальной гипертензией и/или ишемической болезнью сердца (ИБС) с астеническим синдромом (АС).. В открытое сравнительное исследование были включены 120 пациентов в возрасте 54—67 лет с артериальной гипертензией и/или ИБС с АС. Пациенты 1-й группы (. У больных 1-й группы отмечено статистически значимое уменьшение различных проявлений АС. Отличия носили достоверный характер по сравнению как с исходным уровнем, так и со 2-й группой. Установлено эндотелийпротективное действие ЛК и АЛК.. Полученные результаты свидетельствуют, что у таких коморбидных пациентов использование ЛК и АЛК уменьшает выраженность проявлений АС, а установленные эндотелиотропные свойства препаратов позволяют рекомендовать их в составе комплексной персонифицированной терапии пациентов с сердечно-сосудистыми заболеваниями.. Naproxen sodium 440 mg/diphenhydramine 50 mg combination demonstrated improvement in sleep maintenance (WASO) vs. naproxen sodium 550 mg and higher efficiency in average daily pain reduction compared with the comparison groups. The treatment was well tolerated There were no serious or unexpected adverse events reported in the study.. Сравнительный анализ эффективности и безопасности новой комбинации напроксена натрия и дифенгидрамина у пациентов с неспецифическим болевым синдромом в пояснично-крестцовом отделе спины (M54.5 «Боль внизу спины») и нарушением сна (G47.0 «Нарушения засыпания и поддержания сна [бессонница]»).. Проведено проспективное многоцентровое рандомизированное открытое сравнительное в параллельных группах клиническое исследование. Пациенты были рандомизированы в 3 группы. Больные 1-й группы получали напроксен натрия (440 мг) и дифенгидрамин (50 мг), 2-й — напроксен натрия (550 мг), 3-й — парацетамол (1000 мг) и дифенгидрамин (50 мг). Исследуемые препараты пациенты принимали однократно перед сном в течение 3 дней. Все пациенты также принимали 275 мг (1 таблетка) напроксена натрия в качестве препарата фоновой терапии. Первичным критерием эффективности было общее время бодрствования после наступления сна (WASO), измеряемое методом актиграфии. Также использовались критерии оценки продолжительности и качества сна и выраженности боли.. Анализ эффективности проведен для ITT популяции (. Применение комбинации напроксена натрия (440 мг) и дифенгидрамина (50 мг) характеризовалось более выраженным поддержанием сна по сравнению с напроксеном натрия 550 мг и более высокой эффективностью в отношении снижения интенсивности боли по сравнению со 2-й и 3-й группами. Отмечена хорошая переносимость препарата, серьезных нежелательных явлений зарегистрировано не было.

Topics: Acetaminophen; Acetylcarnitine; Acetylcholinesterase; Acids; Acinetobacter baumannii; Acinetobacter Infections; Adaptation, Psychological; Adolescent; Adsorption; Adult; Aged; Alcohol Drinking; Alzheimer Disease; Amikacin; Ammonia; Anaerobiosis; Animals; Anorexia; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Anxiety; Aptamers, Nucleotide; Asthenia; Attention Deficit Disorder with Hyperactivity; Bacterial Proteins; Beryllium; beta-Lactamases; Biofuels; Biomass; Biosensing Techniques; Bismuth; Blister; Body Mass Index; Body Surface Area; Boronic Acids; Brain; Breast Neoplasms; Butyrylcholinesterase; Cannabis; Carbapenems; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Carboxylic Acids; Carcinoma, Hepatocellular; Cardiovascular Diseases; Carnitine; Case-Control Studies; Catalysis; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Child; China; Cholinesterase Inhibitors; Clarithromycin; Clostridioides; Clostridioides difficile; Clostridium Infections; Cohort Studies; Colistin; Colitis; Colon; Coloring Agents; Coronary Artery Bypass; Creatinine; Crystalloid Solutions; Cytokines; Depression; Dextran Sulfate; Dextrans; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Diarrhea; Dietary Supplements; Diphenhydramine; Disease Models, Animal; Disease Outbreaks; Double-Blind Method; Doxorubicin; Drosophila; Drug Tapering; Dysbiosis; Electrons; Escherichia coli; Extracellular Vesicles; Fatigue; Female; Fermentation; gamma-Cyclodextrins; Gastrointestinal Microbiome; Glucose; Graft Survival; Graft vs Host Disease; Head and Neck Neoplasms; Heart Arrest, Induced; Hematopoietic Stem Cell Transplantation; High-Intensity Interval Training; Hippocampus; Humans; Hydrogen-Ion Concentration; Hypertension; Incidence; Interferon-gamma; Italy; Kinetics; Klebsiella Infections; Klebsiella pneumoniae; Lab-On-A-Chip Devices; Lactoferrin; Larva; Length of Stay; Lignin; Liver; Liver Neoplasms; Liver Transplantation; Living Donors; Low Back Pain; Lung; Lung Volume Measurements; Macrophages; Male; Melphalan; Men; Mendelian Randomization Analysis; Meropenem; Methane; Mice; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mitochondrial Proteins; Molecular Docking Simulation; Molecular Structure; Mothers; Motivation; Mycoplasma; Mycoplasma hominis; Mycoplasma Infections; NAD; Nanocomposites; Nanoparticles; Nanotubes, Carbon; Naproxen; Neovascularization, Pathologic; Neurons; Nitrates; Nucleolin; Opuntia; Paratyphoid Fever; Phenotype; Phosphatidylinositol 3-Kinases; Phytochemicals; Plant Extracts; Pregnancy; Prevalence; Prospective Studies; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Wistar; Resveratrol; Retrospective Studies; Rifampin; Risk Factors; RNA, Messenger; Selenium; Sleep; Social Behavior; Soil; Soil Pollutants; Squamous Cell Carcinoma of Head and Neck; Staphylococcus aureus; Structure-Activity Relationship; Suicidal Ideation; Suicide; Superoxide Dismutase-1; Surveys and Questionnaires; Swimming; Syndrome; Tannins; Temperature; Transforming Growth Factor beta; Transplantation Conditioning; Treatment Outcome; Triple Negative Breast Neoplasms; Troponin T; Tumor Microenvironment; United Kingdom; Ureaplasma; Ureaplasma urealyticum; Urinary Tract Infections; Viscum; Waste Disposal Facilities; Wastewater; Water; Water Pollutants, Chemical; Wolfiporia; Young Adult

Proteinuria and dyslipidemia are nonimmune risk factors implicated in the deterioration of kidney function and associated with an increased risk of accelerated atherogenesis. Statin therapy, used for cholesterol reduction, has shown a renoprotective effect in animal models, particularly in cases of proteinuria. This may occur through lipid-independent mechanisms, such as improved endothelial dysfunction/vascular biology, reduced inflammatory cytokine production (transforming growth factor-beta 1 [TGF-beta1]), and regulation of fibrogenic responses. We studied mechanisms of action of agents, such as statins, to change proteinuria, inflammatory parameters, and TGF-beta1 plasma levels in relation to vascular tone.. Fifty-six kidney transplant recipients (30 men and 26 women of overall mean age 54 +/- 13 years) were treated posttransplantation with atorvastatin (10 mg/d) for 12 weeks without renin-angiotensin-system blockade drugs. Inflammatory variables, biochemical parameters, lipid profile, renal function, and TGF-beta1 levels were determined at baseline and at 3 months. Vascular stiffness was evaluated using pulse wave velocity (PWV).. Baseline TGF-beta1 plasma levels were higher among transplant recipients than healthy controls, namely 8.12 ng/mL (range, 5.82-13.12) to 2.55 (range, 1.78- 4.35) (P < .01). Furthermore, the levels remained higher after the treatment with atorvastatin, namely, 7.59 (range, 4.97-12.35) to 2.55 (range, 1.78-4.35) ng/mL (P < .01). Atorvastatin treatment significantly decreased total cholesterol as well as low-density lipoprotein cholesterol plasma levels, but did not modify mean blood pressure (MBP), proteinuria, creatinine clearance, or inflammatory factors. Reduction in TGF-beta1 plasma levels was statistically significant among patients with PWV >9.75 (m/s) (pathology reference value) namely, from 10.7 ng/mL (range, 7.02-13.98) to 6.7 (range, 3.96-11.94) (P = .038). Among older patients, atorvastatin significantly decrease TGF-beta1 plasma levels: from 9.5 ng/mL (range, 6.45-14.44) to 5.65 (range, 3.63-9.48; P < .05). The decreased TGF-beta1 was not related to changes in lipid profiles.. Atorvastatin (10 mg/d) improved the lipid profile and moreover among older patients with worse PWV (>9.75 m/s), TGF-beta1 levels were significantly reduced. Our results suggested that statins displayed potent actions distinct from their hypolipidemic effects.

Topics: Adult; Aged; Atorvastatin; Blood Pressure; Cohort Studies; Dyslipidemias; Female; Glomerular Filtration Rate; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Proteinuria; Pyrroles; Transforming Growth Factor beta

Renin-angiotensin system inhibition is a widely accepted approach to initially deal with proteinuria in IgA nephropathy, while the role of immunosuppressants remains controversial in many instances. A prospective, uncontrolled, open-label trial was undertaken in patients with biopsy-proven IgA nephropathy with proteinuria > 0.5 g/day and normal renal function to assess the efficacy of a combination treatment of angiotensin converting enzyme inhibitors plus angiotensin receptor blockers enalapril valsartan coupled with methylprednisone to decrease proteinuria to levels below 0.5 g/day. Twenty patients were included: Age 37.45 +/- 13.26 years (50% male); 7 patients (35%) were hypertensive; proteinuria 2.2 +/- 1.86 g/day; serum creatinine 1.07 +/- 0.29 mg/dl; mean follow-up 60.10 +/- 31.47 months. IgA nephropathy was subclassified according to Haas criteria. Twelve patients (60%) were class II; seven (35%) were class III and one (5%) class V. All patients received dual renin-angiotensin system blockade as tolerated. Oral methylprednisone was started at 0.5 mg/kg/day for the initial 8 weeks and subsequently tapered bi-weekly until the maintenance dose of 4 mg was reached. Oral steroids were discontinued after 24 weeks (6 months) of therapy but renin-angiotensin inhibition remained unchanged. At 10 weeks of therapy proteinuria decreased to 0.15 +/- 0.07 g/day (P < 0.001) while serum creatinine did not vary: 1.07 +/- 0.28 mg/dl (P = ns). After a mean follow-up of 42.36 +/- 21.56 months urinary protein excretion (0.12 +/- 0.06 g/day) and renal function (serum creatinine 1.06 +/- 0.27 mg/dl) remained stable. No major side effects were reported during the study. Renin-angiotensin blockade plus oral steroids proved useful to significantly decrease proteinuria to < 0.5 g/day in patients with IgA nephropathy without changes in renal function.

Topics: Administration, Oral; Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulonephritis, IGA; Glucocorticoids; Humans; Hypertension; Male; Prednisolone; Prospective Studies; Proteinuria; Renin-Angiotensin System; Transforming Growth Factor beta

Although structural and functional changes of resistance arteries have been proposed to participate in arterial hypertension (HTA) outcome, not all therapies may correct these alterations, even if they normalize the blood pressure (BP). The aim of this study was to investigate the mechanisms of the protection afforded by the angiotensin receptor antagonist losartan in resistance arteries from patients with essential HTA. In all, 22 untreated hypertensive patients were randomized to receive losartan or amlodipine for 1 year and the morphological characteristics of resistance vessels from subcutaneous biopsies were evaluated. Protein expression of connective tissue growth factor (CTGF), transforming growth factor beta (TGF-beta), and collagens III and IV was detected by immunohistochemistry. In comparison with normotensive subjects, resistance arteries from hypertensive patients showed a significant media:lumen (M/L) ratio increment and a higher protein expression of CTGF, TGF-beta, and collagens. After 1 year of treatment, both losartan and amlodipine similarly controlled BP. However, M/L only decreased in patients under losartan treatment, whereas in the amlodipine-treated group this ratio continued to increase significantly. The administration of losartan prevented significant increments in CTGF, TGF-beta, and collagens in resistance arteries. By contrast, amlodipine-treated patients showed a higher vascular CTGF, TGF-beta, and collagen IV staining than before treatment. Our results show that the administration of losartan, but not amlodipine, to hypertensive patients improves structural abnormalities and prevents the production of CTGF and TGF-beta in small arteries, despite similar BP lowering. These data may explain the molecular mechanisms of the better vascular protection afforded by drugs interfering with the renin-angiotensin system.

Topics: Adult; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteries; Connective Tissue Growth Factor; Humans; Hypertension; Immediate-Early Proteins; Immunohistochemistry; Intercellular Signaling Peptides and Proteins; Losartan; Middle Aged; Reference Values; Transforming Growth Factor beta; Vascular Resistance

In this study we evaluated the effect of a dual blockade with enalapril and losartan on the reduction of overt macroproteinuria and its potential mechanism(s) in hypertensive patients with type 2 diabetes. Twenty-six hypertensive patients with type 2 diabetes at the baseline were administered 5 mg of enalapril once daily for 12 weeks. At the beginning of the study, the subjects were assigned to receive an add-on of 50 mg of losartan once daily or 5 mg of enalapril once daily for another 12 weeks. Blood samples were collected at the baseline, at the beginning, and at the end of the study for the measurement of laboratory parameters, and these data, including blood pressure, were compared between the two groups. Treatment with 5 mg of enalapril significantly decreased the systolic blood pressure level in both groups, and the addition of losartan and/or enalapril further decreased the levels. There was no difference in blood pressure between the two groups. However, the addition of losartan, but not enalapril, significantly decreased the urinary protein excretion level, plasma aldosterone, and hypersensitive-C-reactive protein at the end of the study. The results established that the dual blockade of angiotensin II with enalapril and losartan has a greater clinical benefit for high-risk patients with hypertension and advanced diabetic nephropathy.

Topics: Aged; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; C-Reactive Protein; Cystatin C; Cystatins; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Female; Humans; Hypertension; Losartan; Male; Middle Aged; Natriuretic Peptide, Brain; Proteinuria; Transforming Growth Factor beta

Angiotensin II, via the angiotensin II type 1 (AT1) receptor, may mediate myocardial fibrosis and myocyte hypertrophy seen in hypertensive left ventricular (LV) hypertrophy through production of transforming growth factor beta1 (TGF-beta1); AT1-receptor antagonists reverse these changes. The TGF-beta1 G + 915C polymorphism is associated with interindividual variation in TGF-beta1 production. No study has yet determined the impact of this polymorphism on the response to antihypertensive treatment.. We aimed to determine whether the TGF-beta1 G + 915C polymorphism was related to change in LV mass during antihypertensive treatment with either an AT1-receptor antagonists or a beta1-adrenoceptor blocker. The polymorphism was hypothesized to have an impact mainly on the irbesartan group.. We determined the association between the TGF-beta1 genotype and regression of LV mass in 90 patients with essential hypertension and echocardiographically diagnosed LV hypertrophy, randomized in a double-blind study to receive treatment for 48 weeks with either the AT1-receptor antagonist irbesartan or the beta1-adrenoceptor blocker atenolol.. Irbesartan-treated patients who were carriers of the C-allele, which is associated with low expression of TGF-beta1, responded with a markedly greater decrease in LV mass index (LVMI) than subjects with the G/G genotype (adjusted mean change in LVMI -44.7 g/m2 vs. -22.2 g/m2, p = 0.007), independent of blood pressure reduction. No association between genotype and change in LVMI was observed in the atenolol group.. The TGF-beta1 G + 915C polymorphism is related to the change in LVMI in response to antihypertensive treatment with the AT1-receptor antagonist irbesartan.

Topics: Antihypertensive Agents; Atenolol; Biphenyl Compounds; Double-Blind Method; Female; Genotype; Humans; Hypertension; Hypertrophy, Left Ventricular; Irbesartan; Linear Models; Male; Polymorphism, Genetic; Sweden; Tetrazoles; Transforming Growth Factor beta; Treatment Outcome

Transforming growth factor-beta1 (TGF-beta1) is the major profibrotic cytokine involved in many renal diseases, and urinary TGF-beta1 reflects intrarenal TGF-beta1 production. Urinary TGF-beta1 excretion is reported to be significantly increased in patients with immunoglobulin A (IgA) nephropathy. The aim of the present study was to compare the effects of losartan and amlodipine on proteinuria, as well as on serum and urine TGF-beta1 levels in IgA nephropathy patients with hypertension and proteinuria.. The initial 4 week washout period was followed by 12 weeks of active treatment, in which patients were randomized to once-daily treatment with losartan 50 mg (group 1, n=20) or amlodipine 5 mg (group 2, n=16). Urinary protein and TGF-beta1 excretion, serum TGF-beta1 and other clinical parameters were determined at baseline and during 12 weeks of active treatment.. Both treatments controlled blood pressure (BP) to a similar degree, and renal function and other biochemical parameters did not change during the study period. Urinary protein and TGF-beta1 excretions were significantly elevated in IgA nephropathy patients. Losartan significantly reduced urinary protein (from 2.3+/-1.5 g/day at baseline to 1.2+/-1.5 g/day at 12 weeks, P<0.05) and urinary TGF-beta1 excretion (from 31.2+/-14.0 pg/mg creatinine at baseline to 22.1+/-13.5 pg/mg creatinine at 12 weeks, P<0.05). In contrast, amlodipine had no affect on urinary protein and TGF-beta1 excretion. Both losartan and amlodipine failed to reduce serum TGF-beta1 levels.. Losartan and amlodipine, with similar control of BP, showed different effects on urine protein or TGF-beta1 excretion. Whereas losartan improved both urinary parameters, amlodipine did not. These differences might be important for the management of IgA nephropathy.

Topics: Adult; Amlodipine; Antihypertensive Agents; Blood Pressure; Female; Glomerulonephritis, IGA; Humans; Hypertension; Losartan; Male; Middle Aged; Proteinuria; Transforming Growth Factor beta; Transforming Growth Factor beta1; Treatment Outcome

Cyclosporin is a powerful stimulator of oxidative stress signaling, leading to TGFbeta production, NO degradation, endothelial dysfunction, hypertension and post-transplant nephropathy. Carvedilol, alpha1-beta-blocker with strong antioxidant activity, may interfere with this chain of events. Therefore, we measured monocyte ecNOS, TGFbeta and heme oxygenase-1 (HO-1) mRNA level and plasma nitrite/nitrate, 3-nitrotyrosine, an estimate of peroxynitrite, and total plasma antioxidant power in kidney-transplanted patients with post-transplant hypertension, before and after treatment with carvedilol, 25 - 50 mg o.d. orally for 4 months (n = 15). The dihydropyridine calcium channel blocker nifedipine (n = 10) was used as comparator antihypertensive drug. Blood pressure fell to a similar extent with both drugs. Carvedilol increased plasma antioxidant power and HO-1 mRNA and reduced 3-nitrotyrosine and TGFbeta mRNA levels, while the same was not observed with nifedipine. Monocyte ec NOS mRNA levels and plasma nitrite/nitrate were higher in the patients than in a normotensive healthy control group and were unaffected by either treatment. In conclusion, carvedilol reduces the oxidative stress and corrects the altered cellular signaling mediated by oxidative stress in CsA-induced post-transplant hypertension. Therefore, it may prevent long-term complications, such as endothelial dysfunction, fibrogenesis and post-transplant nephropathy by decreasing NO degradation and production of TGFbeta, a key fibrogenic cytokine, and by activating HO-1 production.

Topics: Adrenergic beta-Antagonists; Adult; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Carbazoles; Carvedilol; Cyclosporine; Drug Evaluation; Female; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Membrane Proteins; Middle Aged; Nifedipine; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Oxidative Stress; Postoperative Complications; Propanolamines; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta; Treatment Outcome; Tyrosine

Progression of renal failure, despite renoprotection with angiotensin-converting enzyme (ACE) inhibitors in patients with proteinuric nephropathies, may be caused by persistent renal production of transforming growth factor-beta1 (TGF-beta1) through the angiotensin II subtype 1 (AT1) receptors. We tested the hypothesis that AT1-receptor blocker therapy added to a background of chronic maximal ACE inhibitor therapy will result in a reduction in urinary TGF-beta1 levels in such patients. Sixteen patients completed a two-period, crossover, randomized, controlled trial, details of which have been previously reported. All patients were administered lisinopril, 40 mg/d, with either losartan, 50 mg/d, or placebo. Blood pressure (BP) was measured using a 24-hour ambulatory BP monitor. Overnight specimens of urine were analyzed for urine TGF-beta1, protein, and creatinine concentrations. Mean age of the study population was 53 +/- 9 (SD) years; body mass index, 38 +/- 5.7 kg/m2; seated BP, 156 +/- 18/88 +/- 12 mm Hg; and urine protein excretion, 3.6 +/- 0.71 g/g of creatinine. Twelve patients had diabetic nephropathy, and the remainder had chronic glomerulonephritis. At baseline, urinary TGF-beta1 levels were significantly increased in the study population compared with healthy controls (13.2 +/- 1.2 versus 1.7 +/- 1.1 ng/g creatinine; P < 0.001). There was a strong correlation between baseline urine protein excretion and urinary TGF-beta1 level (r2 = 0.53; P = 0.001), as well as systolic BP and urinary TGF-beta1 level (r2 = 0.57; P < 0.001). After 4 weeks of add-on losartan therapy, there was a 38% (95% confidence interval [CI], 16% to 55%) decline in urinary TGF-beta1 levels (13.3 [95% CI, 11.4 to 15.5] to 8.2 pg/mg creatinine [95% CI, 6.2 to 10.7]). The reduction in urinary TGF-beta1 levels occurred independent of changes in mean urinary protein excretion or BP. Thus, proteinuric patients with renal failure, despite maximal ACE inhibition, had increased urinary levels of TGF-beta1 that improved over 1 month of add-on therapy with losartan. We speculate that dual blockade with losartan and an ACE inhibitor may provide additional renoprotection by decreasing renal production of TGF-beta1.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Drug Therapy, Combination; Female; Humans; Hypertension; Kidney Failure, Chronic; Lisinopril; Losartan; Male; Middle Aged; Proteinuria; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta) is a prosclerotic growth factor implicated in the pathogenesis of diabetic nephropathy. In addition to high glucose, other factors implicated in renal fibrosis and increased TGF-beta synthesis include angiotensin II and high dietary sodium intake. The aim of this study was to examine the effect of angiotensin receptor blockade (ARB) and dietary sodium restriction on the plasma concentration and urinary excretion of TGF-beta in hypertensive patients with type 2 diabetes and elevated albumin excretion rate (AER).. Twenty-one subjects with hypertension and AER between 10 and 200 microg/min were randomized to receive either 50 mg losartan daily (n = 11) or placebo (n = 10). Drug therapy was given in two 4-week phases, separated by a 4-week washout period. In the last 2 weeks of each phase, patients were assigned to regular- or low-sodium diets in random order. Parameters measured at week 0 and 4 of each phase included plasma TGF-beta concentration, TGF-beta urinary excretion, AER, clinic mean arterial blood pressure, and urinary sodium excretion.. Plasma TGF-beta was unaffected by losartan treatment or sodium intake. In the losartan group, urinary TGF-beta excretion decreased by 23.2% (-39.2 and 13.6) [median (interquartile range)] and 38.5% (-46.8 and -6.1) in the regular- and low-sodium phases, respectively (P < 0.05 for drug effect). In the placebo group, median changes of 0.0% (-12.1 and 44.4) and 0.0% (-29.2 and 110.7) occurred in the regular- and low-sodium phases, respectively. Sodium restriction did not affect urinary TGF-beta excretion in either losartan- or placebo-treated patients (P = 0.54 for overall dietary effect), and there was no evidence of interaction between drug and diet (P = 0.29).. In hypertensive type 2 diabetic patients with elevated AER, the ARB losartan, but not sodium restriction, reduced urinary TGF-beta excretion. These data suggest that the renoprotective effects of losartan in patients with type 2 diabetes and nephropathy may include a reduction in renal TGF-beta production.

Topics: Albuminuria; Analysis of Variance; Angiotensin Receptor Antagonists; Antihypertensive Agents; Blood Pressure; Body Mass Index; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diet, Sodium-Restricted; Female; Glycated Hemoglobin; Humans; Hypertension; Losartan; Male; Middle Aged; Placebos; Regression Analysis; Sodium; Transforming Growth Factor beta

The aim of the present study was to determine the effect of losartan on transforming growth factor-beta1 (TGF-beta1) plasma levels and urinary albumin excretion (UAE) in patients with type 2 diabetes mellitus, mild hypertension and microalbuminuria.. Fourteen patients (eight males, aged 55+/-6 years) with type 2 diabetes mellitus, mild arterial hypertension and microalbuminuria, participating in an open, uncontrolled, pilot study were included. Patients were treated for 8 weeks with losartan. TGF-beta1 plasma levels, UAE and 24-h blood pressure monitoring were determined at baseline and at 4 and 8 weeks.. At 4 and 8 weeks of treatment, a reduction was observed in TGF-beta1 plasma levels (5.5+/-4.5 vs 2.0+/-0.6 and 2.6+/-1.0 ng/ml, P<0.005), UAE (96+/-65 vs 59+/-59 and 64+/-47 microg/min, P<0.01), 24-h systolic blood pressure (136+/-9 vs 129+/-9 and 130+/-10 mmHg, P<0.01) and 24-h diastolic blood pressure (77+/-9 vs 74+/-8 and 74+/-7 mmHg, P<0.03). Stratifying the patients by baseline TGF-beta1, seven had TGF-beta1 plasma values higher than normal controls. At 4 and 8 weeks, they showed a marked reduction in TGF-beta1 values (9.0+/-3.9 to 2.1+/-0.7 and 2.5+/-0.7 ng/ml, P<0.01) and UAE (106+/-83 to 49+/-42 and 38+/-26 microg/min, P<0.05), with good correlation between the percentage reduction of both parameters (r=0.83, P<0.01). The remaining seven patients, with normal baseline TGF-beta1 plasma levels, showed no change in TGF-beta1 plasma levels and UAE after treatment.. Treatment with losartan decreases TGF-beta1 plasma values and UAE in type 2 diabetes mellitus patients with high baseline TGF-beta1 levels, suggesting that TGF-beta1 may be a marker to detect patients who may particularly benefit from renin-angiotensin system blockade.

Topics: Albuminuria; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diastole; Female; Humans; Hypertension; Losartan; Male; Middle Aged; Pilot Projects; Systole; Transforming Growth Factor beta

We investigated whether a relationship exists between circulating transforming growth factor beta -1 (TGF-beta(1)), collagen type I metabolism, microalbuminuria, and left ventricular hypertrophy in essential hypertension and whether the ability of the angiotensin II type 1 receptor antagonist losartan to correct microalbuminuria and regress left ventricular hypertrophy in hypertensives is related to changes in TGF-beta(1) and collagen type I metabolism. The study was performed in 30 normotensive healthy controls and 30 patients with never-treated essential hypertension classified into 2 groups: those with microalbuminuria (urinary albumin excretion >30 and <300 mg/24 h) associated with left ventricular hypertrophy (left ventricular mass index >116 g/m(2) for men and >104 g/m(2) for women) (group B; n=17) and those without microalbuminuria or left ventricular hypertrophy (group A; n=13). The measurements were repeated in all patients after 6 months of treatment with losartan (50 mg once daily). The serum concentration of TGF-beta(1) was measured by a 2-site ELISA method, and the serum concentrations of carboxy-terminal propeptide of procollagen type I (a marker of collagen type I synthesis) and carboxy-terminal telopeptide of collagen type I (a marker of collagen type I degradation) were measured by specific radioimmunoassays. The duration of hypertension and baseline values of blood pressure were similar in the 2 groups of patients. No differences in serum TGF-beta(1), carboxy-terminal propeptide of procollagen type I, and carboxy-terminal telopeptide of collagen type I were found between normotensives and group A of hypertensives. Serum TGF-beta(1), carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I were increased (P<0.05) in group B of hypertensives compared with group A of hypertensives and normotensives. No differences in carboxy-terminal telopeptide of collagen type I were found among the 3 groups of subjects. After treatment with losartan, microalbuminuria and left ventricular hypertrophy persisted in 6 patients (then considered nonresponders) and disappeared in 11 patients (then considered responders) from group B. Compared with nonresponders, responders exhibited similar control of blood pressure and higher (P<0.05) blockade of angiotensin II type 1 receptors (as assessed by a higher increase in plasma levels of angiotensin II). Wh

Topics: Albuminuria; Angiotensin II; Antihypertensive Agents; Collagen; Collagen Type I; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Losartan; Male; Middle Aged; Peptide Fragments; Peptides; Procollagen; Transforming Growth Factor beta; Transforming Growth Factor beta1; Treatment Outcome

Transforming growth factor-beta 1 (TGF-beta 1) plays an important role in the modulation of cellular growth and differentiation and the production and degradation of the extracellular matrix. A number of experimental results suggest that TGF-beta 1 may be involved in cardiovascular physiopathology. In the present study, we assessed whether the TGF-beta 1 gene is a candidate gene for coronary heart disease or hypertension. We screened the coding region and 2181 bp upstream of the TGF-beta gene for polymorphisms and identified seven polymorphisms: 3 in the upstream region of the gene at positions -988, -800, and -509 from the first transcribed nucleotide; 1 in a nontranslated region at position +72; 2 in the signal peptide sequence Leu10-->Pro, Arg25-->Pro; and 1 in the region of the gene coding for the precursor part of the protein not present in the active form, Thr263-->Ile. We analyzed these TGF-beta 1 polymorphisms in 563 patients with myocardial infarction and 629 control subjects from four regions in Northern Ireland and France. The Pro25 allele was more frequent in patients than in control subjects in Belfast (P < .01) and Strasbourg (P < .05). The TGF-beta 1 polymorphisms were not associated with the degree of angiographically assessed coronary artery disease in patients. The presence of a Pro25 allele was associated with a lower systolic pressure in the four control groups (P < .002), and a history of hypertension was significantly less frequent in homozygotes or heterozygotes for Pro25 than in hormozygotes for Arg25 (odds ratio, 0.43, 95% confidence interval, 0.19 to 0.92; P < .03). Since the Pro25 allele was associated with an increased risk of myocardial infarction and a reduced risk of hypertension, we favor a cautious interpretation of these apparently inconsistent results. Other studies will need to verify whether these associations are real.

Topics: Adult; Alleles; Blood Pressure; Genotype; Humans; Hypertension; Male; Middle Aged; Myocardial Infarction; Polymorphism, Genetic; Transforming Growth Factor beta

Oxidative stress and MMP activity are found in the hearts and arteries in hypertension and contribute to the resulting hypertrophy and dysfunction. Quercetin is a flavonoid that reduces MMP-2 activity and ameliorates hypertrophic vascular remodeling of hypertension. The hypothesis is that treatment of hypertensive rats with quercetin ameliorates coronary maladaptive remodeling and decreases hypertrophic cardiac dysfunction by decreasing oxidative stress and MMP activity. Male Sprague-Dawley two-kidney, one-clip (2K1C) and Sham rats were treated with quercetin (10 mg/kg/day) or its vehicle for 8 weeks by gavage. Rats were analyzed at 10 weeks of hypertension. Systolic blood pressure (SBP) was examined by tail-cuff plethysmography. Cardiac left ventricles were used to determine MMP activity by in situ zymography and oxidative stress by dihydroethidium. Immunofluorescence was performed to detect transforming growth factor (TGF)-β and nuclear factor kappa B (NFkB). Morphological analyses of heart and coronary arteries were done by H&E and picrosirius red, and cardiac function was measured by Langendorff. SBP was increased in 2K1C rats, and quercetin did not reduce it. However, quercetin decreased both oxidative stress and TGF-β in the left ventricles of 2K1C rats. Quercetin also decreased the accentuated MMP activity in left ventricles and coronary arteries of 2K1C rats. Quercetin ameliorated hypertension-induced coronary arterial hypertrophic remodeling, although it did not reduce cardiac hypertrophic remodeling and dysfunction. Quercetin decreases cardiac oxidative stress and TGF-β and MMP activity in addition to improving coronary remodeling, yet does not ameliorate cardiac dysfunction in 2K1C rats.

Topics: Animals; Blood Pressure; Cardiomegaly; Coronary Vessels; Hypertension; Hypertension, Renovascular; Kidney Diseases; Male; Quercetin; Rats; Rats, Sprague-Dawley; Rats, Wistar; Transforming Growth Factor beta

Topics: Animals; Desoxycorticosterone Acetate; Fibrosis; Hypertension; Hypertension, Renal; Kidney; Mice; Transforming Growth Factor beta

Fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease; however, the mechanisms underlying the effect of FGF23 on cardiac function remain to be investigated. Herein, we studied the effect of continuous intravenous (CIV) FGF23 loading in a deoxycorticosterone acetate (DOCA)-salt mouse model with mild chronic kidney disease and hypertension as well as heart failure with a preserved ejection fraction. Wild-type male mice were randomly allocated to 4 groups: normal control, vehicle-treated DOCA-salt mice, FGF23-treated DOCA-salt mice, and FGF23- and calcitriol-treated DOCA-salt mice. The DOCA-salt mice received the agents via the CIV route for 10 days using an infusion minipump. DOCA-salt mice that received FGF23 showed a marked increase in the serum FGF23 level, and echocardiography in these mice revealed heart failure with a preserved ejection fraction. These mice also showed exacerbation of myocardial fibrosis, concomitant with an inverse and significant correlation with Cyp27b1 expression. Calcitriol treatment attenuated FGF23-induced cardiac fibrosis and improved diastolic function via inhibition of transforming growth factor-β signaling. This effect was independent of the systemic and local levels of FGF23. These results suggest that CIV FGF23 loading exacerbates cardiac fibrosis and that locally abnormal vitamin D metabolism is involved in this mechanism. Calcitriol attenuates this exacerbation by mediating transforming growth factor-β signaling independently of the FGF23 levels.

Topics: Animals; Blood Pressure; Calcitriol; Desoxycorticosterone Acetate; Fibroblast Growth Factor-23; Fibrosis; Heart Failure; Hypertension; Male; Mice; Renal Insufficiency, Chronic; Transforming Growth Factor beta; Transforming Growth Factors

To investigate the correlation of inducible co-stimulatory molecules (ICOS) with mesenteric vascular endothelial- mesenchymal transition (EndMT) and sclerosis in spontaneously hypertensive rats (SHR).. Twenty 4-week-old WKY rats and 20 SHRs of the same strain were both randomly divided into 4 groups for observation at 4, 6, 10 and 30 weeks of age. ICOS expression frequency in rat spleen CD4. Compared with the control WKY rats, the SHRs began to show significantly increased systolic blood pressure and ICOS expression frequency on CD4. ICOS play an important pathogenic role in EndMT and sclerosis of mesenteric vessels in essential hypertension by mediating related immune responses.

Topics: Animals; Blood Pressure; Hypertension; Interleukin-17; Mesentery; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Sclerosis; Transforming Growth Factor beta

Renal fibrosis is a crucial pathological feature of hypertensive renal disease (HRD). In-depth analysis of the pathogenesis of fibrosis is of great significance for the development of new drugs for the treatment of HRD. USP25 is a deubiquitinase that can regulate the progression of many diseases, but its function in the kidney remains unclear. We found that USP25 was significantly increased in human and mice HRD kidney tissues. In the HRD model induced by Ang II, USP25

Topics: Angiotensin II; Animals; Deubiquitinating Enzymes; Fibrosis; Humans; Hypertension; Hypertension, Renal; Mice; Signal Transduction; Transforming Growth Factor beta; Ubiquitin Thiolesterase

The crosstalk between the renin-angiotensin system and Adenosine monophosphate-activated protein kinase (AMPK) gained significant interest due to their involvement in the pathogenesis of several cardiovascular diseases. Angiotensin II (Ang II) plays a crucial role in developing cardiac remodelling by inducing energy imbalance, inflammation, oxidative and endoplasmic reticulum stress, and transforming growth factor-β (TGF-β)-induced fibrosis. Ang II directly or through extracellular signal-regulated kinase (ERK) activation impairs AMPK signalling with well-known antioxidant, anti-inflammatory, and anti-fibrotic effects.. This study aimed to investigate the role of bempedoic acid, a novel antihyperlipidemic drug, in attenuating hypertension-induced cardiac remodelling in rats by modulating Ang II-induced damage and activating the AMPK signalling pathway.. Sixty adult male Sprague Dawley rats were randomly allocated into the Sham control group, Hypertensive group, Captopril group (30 mg/kg), and Bempedoic acid group (30 mg/kg). Hypertension was induced by left renal artery ligation in all groups except the Sham control group. Treatment with captopril and bempedoic acid started 14 days post-surgy and lasted two weeks. Finally, Hemodynamic measurements and electrocardiographic examination were done followed by heart tissue samples collection for biochemical, histopathological, and immunohistochemical examinations.. Bempedoic acid preserved the cardiac function and electrocardiogram patterns. It inhibited endoplasmic reticulum stress, exhibited antioxidant activity, and increased endothelial nitric oxide synthase activity. Bempedoic acid interfered with ERK signalling pathways, including nuclear factor-κB and TGF-β, exerting anti-inflammatory and anti-fibrotic effects.. These findings indicate the cardioprotective and antihypertrophic activity of bempedoic acid, which are suggested to result from energy-independent AMPK downstream signalling activation.

Topics: AMP-Activated Protein Kinases; Angiotensin II; Animals; Captopril; Hypertension; Hypertension, Renovascular; Male; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Ventricular Remodeling

An inappropriate accumulation of fibrillar collagen is a common pathologic feature of early aged hypertensive heart disease, but little information regarding the effects of exercise training on cardiac fibrosis in hypertension is available. The purpose of this study was to evaluate the effects of exercise training on cardiac fibrotic pathways in early aged hypertensive rats.. Masson's trichrome staining and Western blotting were performed on the excised left ventricle from twenty male spontaneously hypertensive rats at age of 48 weeks, which were randomly divided into either a sedentary hypertensive group (SHR) or exercise hypertensive group (SHR-EX, running on a treadmill running occurred 5 days/week for 60 min/day, for 12 weeks), and from age-matched male Wistar-Kyoto normotensive controls (WKY).. Exercise training suppresses early aged hypertensive heart-induced LOX-2/TGF-β-mediated fibrotic pathways associated with decreasing AT

Topics: Animals; Exercise Therapy; Fibrosis; Heart Diseases; Hypertension; Male; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Transforming Growth Factor beta

The Preeclampsia (PE) molecular mechanisms are not fully revealed and different biological processes are involved in the pathogenesis of PE. We aimed to evaluate adenosine and hypoxia-related signaling molecules in PE patients in the current study.. Decidua tissue and peripheral blood samples were taken from 25 healthy pregnant and 25 PE women at delivery time. CD39, CD73, and Hypoxia-inducible factor-alpha (HIF-α) were evaluated in mRNA and protein level using real-time PCR and western blotting techniques, respectively. Also, miR-30a, miR-206, and miR-18a expression were evaluated by real-time PCR. At last, secretion levels of IGF and TGF-β in the taken serum of blood samples were measured by ELISA.. Our results revealed that Expression of CD39 is decreased in PE cases versus healthy controls at mRNA and protein levels (p = 0.0003 for both). CD73 and HIF-α showed an increased level of expression in PE patients at RNA and protein status (p = 0.0157 and p < 0.0001 for protein evaluation of CD73 and HIF-α, respectively). The miRNA-30a (p = 0.0037) and miR-206 (p = 0.0113) showed elevated expression in the decidua of the PE group. The concentration of secreted IGF-1 (p = 0.0002) and TGF-β (p = 0.0101) in serum samples of PE cases compared to the healthy group were decreased.. In conclusion, our results showed that aberrant expression of molecules that are involved in ATP catabolism and the hypoxic conditions is observed in PE cases and involved in their hypertension and inflammation could be served as PE prognosis by more confirming in comprehensive future studies. miR-206 and miR-30a play a role by regulating CD39 and CD73 as molecules that are involved in ATP catabolism as well as regulating the production of IGF-1 in the process of hypertension, which is the main feature in patients with preeclampsia. On the other hand, decreased level of miR-18a lead to upregulation of HIF-1a, and the consequence condition of hypoxia increases hypertension and inflammation in these patients.

Topics: Adenosine Triphosphate; Decidua; Female; Humans; Hypertension; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inflammation; Insulin-Like Growth Factor I; MicroRNAs; Pre-Eclampsia; Pregnancy; Pregnant Women; RNA, Messenger; Transforming Growth Factor beta

In this study, we aimed to target two molecules, transforming growth factor-beta (TGF-β) and dynamin to explore their roles in blood-brain barrier (BBB) disruption in hypertension.. For this purpose, angiotensin (ANG) II-induced hypertensive mice were treated with SB-431542, an inhibitor of the ALK5/TGF-β type I receptor, and dynasore, an inhibitor of dynamin. Albumin-Alexa fluor 594 was used to assess BBB permeability. The alterations in the expression of claudin-5, caveolin (Cav)-1, glucose transporter (Glut)-1, and SMAD4 in the cerebral cortex and the hippocampus were evaluated by quantification of immunofluorescence staining intensity.. ANG II infusion increased BBB permeability to albumin-Alexa fluor 594 which was reduced by SB-431542 (P < 0.01), but not by dynasore. In hypertensive animals treated with dynasore, claudin-5 immunofluorescence intensity increased in the cerebral cortex and hippocampus while it decreased in the cerebral cortex of SB-431542 treated hypertensive mice (P < 0.01). Both dynasore and SB-431542 prevented the increased Cav-1 immunofluorescence intensity in the cerebral cortex and hippocampus of hypertensive animals (P < 0.01). SB-431542 and dynasore decreased Glut-1 immunofluorescence intensity in the cerebral cortex and hippocampus of mice receiving ANG II (P < 0.01). SB-431542 increased SMAD4 immunofluorescence intensity in the cerebral cortex of hypertensive animals, while in the hippocampus a significant decrease was noted by both SB-431542 and dynasore (P < 0.01).. Our data suggest that inhibition of the TGFβ type I receptor prevents BBB disruption under hypertensive conditions. These results emphasize the therapeutic potential of targeting TGFβ signaling as a novel treatment modality to protect the brain of hypertensive patients.

Topics: Albumins; Angiotensin II; Animals; Benzamides; Blood-Brain Barrier; Claudin-5; Dioxoles; Dynamins; Hydrazones; Hypertension; Mice; Receptor, Transforming Growth Factor-beta Type I; Transforming Growth Factor beta

The Hippo/YAP (yes-associated protein) pathway is an important signaling pathway to control organ development and tissue homeostasis. YAP is a downstream effector of the Hippo pathway and a critical mediator of mechanic stress. Hypertensive nephropathy is characterized with glomerular sclerosis stiffness and renal fibrosis. The present study investigated the role of YAP pathway in angiotensin (Ang) II hypertensive renal injury by using YAP activation inhibitor verteporfin. Ang II increased the protein expression of YAP in renal nucleus fraction, decreased phospho-YAP, and phospho-LATS1/2 (large tumor suppressors 1 and 2) expressions in renal cytoplasmic fraction, suggesting Ang II activation of renal YAP. Ang II significantly increased systolic blood pressure (SBP), proteinuria, glomerular sclerosis, and fibrosis; treatment with verteporfin attenuated Ang II-induced proteinuria and renal injury with a mild reduction in SBP. Moreover, Ang II increased the protein expressions of inflammatory factors including tumor necrosis factor α, interleukin 1β, and monocyte chemoattractant protein-1, and profibrotic factors including transforming growth factor β, phospho-Smad3 and fibronectin. Verteporfin reversed abovementioned Ang II-induced molecule expressions. Our results for the first time demonstrate that the activation of the YAP pathway promotes hypertensive renal inflammation and fibrosis, which may promote hypertensive renal injury. YAP may be a new target for prevention and treatment of hypertensive renal diseases.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Blood Pressure; Chemokine CCL2; Fibrosis; Hypertension; Hypertension, Renal; Male; Mice; Mice, Inbred C57BL; Nephritis; Photosensitizing Agents; Protein Serine-Threonine Kinases; Signal Transduction; Transforming Growth Factor beta; Vasoconstrictor Agents; Verteporfin; YAP-Signaling Proteins

Preeclampsia (PE) is commonly considered as a placental disorder in pregnancy. Until now, the etiology and pathological mechanism of PE have remained ambiguous. Although PE can lead to a variety of maternal and infant complications, there are still no effective treatments. This study aimed to explore the correlation between the novel polypeptide COL-4A1 and PE, and to identify the underlying mechanism by which this polypeptide may function and to explore new therapeutic targets for PE. A rat model of PE was established and used to verify the function of the polypeptide COL-4A1 in vivo. Additionally, human umbilical vascular endothelial cells (HUVECs) were cultured with or without COL-4A1 and TNF-α (20 ng/ml). Cell Counting Kit-8 (CCK-8), wound-healing, Transwell and tube formation assays were used to evaluate cell proliferation, migration and angiopoiesis. RNA sequencing and mass spectrometry were conducted to explore the underlying downstream mechanism of COL-4A1. In vivo, COL-4A1 increased blood pressure and elevated the risk of fetal growth restriction (FGR) which was induced by lipopolysaccharide (LPS) in the rat model. In vitro, COL-4A1 significantly inhibited the proliferation and migration of HUVECs. After culture with COL-4A1, compared to control group the adhesive ability and level of reactive oxygen species (ROS) were enhanced and tube formation ability was decreased. Furthermore, Western blotting (WB) and pull-down assays were conducted to explore the underlying mechanism by which COL-4A1 functions, and the TGF-β/PI3K/AKT pathway was identified as the potential pathway involved in its effects. In summary, these results revealed that the polypeptide COL-4A1 caused PE-like symptoms in cells and a rat model. Through the TGF-β/PI3K/AKT pathway, COL-4A1 interferes with the pathogenesis of PE. Thus COL-4A1 is expected to become a potential target of PE, providing a basis for exploring the treatment of PE.

Topics: Animals; Cell Movement; Cell Proliferation; Collagen Type IV; Female; Fetal Growth Retardation; Human Umbilical Vein Endothelial Cells; Humans; Hypertension; Male; Peptides; Phosphatidylinositol 3-Kinases; Pre-Eclampsia; Pregnancy; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Signal Transduction; Transforming Growth Factor beta

Treating ventricular remodeling continues to be a clinical challenge. Studies have shown that hypertension is one of the most common causes of ventricular remodeling, and is a major cause of cardiovascular risk in adults. Here, we report that Tongsaimai (TSM), a Chinese traditional medicine, could inhibit arterial pressure and left ventricular pressure to improve hemodynamic abnormalities in rats impaired by abdominal aortic constriction (AAC). Administration of TSM significantly reduced the heart mass index and the left ventricular mass index significantly in AAC rats. TSM could also markedly ameliorate cardiac collagen deposition and reduce the concentration of hydroxyproline in the heart of AAC rats. Moreover, TSM alleviated cardiac histomorphology injury resulting from AAC, including reducing cardiomyocyte hypertrophy, fibrous connective tissue hyperplasia, cardiomyocyte apoptosis, replacement fibrosis and the disorders of myocardial myofibrils, intercalated discs, mitochondria and mitochondrial crista. In addition, the levels of transforming growth factor (TGF) - β and inflammation-related molecules including tumor necrosis factor-α (TNF-α), which were over-expressed with AAC, were decreased by STM. In conclusion, STM could reverse the hypertension and left ventricular remolding caused by abdominal aortic constriction in rats.

Topics: Animals; Antihypertensive Agents; Aorta, Abdominal; Arterial Pressure; Cardiomegaly; Collagen; Constriction; Drugs, Chinese Herbal; Hypertension; Male; Myocardium; Rats, Sprague-Dawley; Renin-Angiotensin System; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Ventricular Remodeling

Myocardial fibrosis (MF) is an unavoidable complication in patients with hypertensive heart disease. Valsartan, a widely used antihypertensive drug, was reported to inhibit MF. Deficiency in the 5-hydroxytryptamine (5-HT, serotonin) transporter gene has been proven to cause MF. Long-term sympathetic nerve excitability activates renin angiotensin aldosterone system leading to MF. Tandospirone, a partial agonist of the 5-HT1A receptor, has been commonly used to relieve psychiatric symptoms. However, there is limited evidence on the combination of valsartan and tandospirone for the treatment of MF. Therefore, we investigated the synergistic effect of tandospirone on the anti-MF activity of valsartan in spontaneously hypertensive rats (SHRs).. Systolic blood pressure (SBP) of SHRs (12-week-old) was measured weekly using the tail-cuff method for eight weeks; the left ventricular was collected and weighted for calculation of the left ventricular mass index (LVMI). The myocardial histopathology of left ventricle was evaluated in rats by hematoxylin and eosin (H&E) and Mason's trichrome staining assays. The mRNA and protein expressions of transforming growth factor β (TGF-β1), Sma- and Mad-related protein 3 (Smad3), and fibronectin (Fn) were investigated by real time PCR, immunohistochemistry, and Western blotting analysis, respectively.. Tandospirone (40 mg/kg) could significantly improve the effect of valsartan (30 mg/kg) in decreasing the SBP of SHRs and lower the ratio of the LVMI in SHRs, compared to that of rats treated with valsartan or tandospirone alone. Tandospirone could also enhance the valsartan-induced reduction in collagen deposition in the myocardial tissues of SHRs. Furthermore, tandospirone could enhance the effect of valsartan on downregulating the expression levels of TGF-β1, Smad3, and Fn at both mRNA and protein levels.. We report for the first time that tandospirone could improve the anti-MF efficacy of valsartan via the TGF-β1/Smad3 signaling pathway in SHRs. Our findings may provide valuable insight into the scientific rationale for combining tandospirone and valsartan in the treatment of MF clinically.

Topics: Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Cardiomyopathies; Drug Synergism; Fibrosis; Gene Expression; Hypertension; Immunohistochemistry; Isoindoles; Male; Models, Biological; Myocardium; Piperazines; Pyrimidines; Rats; Rats, Inbred SHR; Serotonin Receptor Agonists; Smad3 Protein; Transforming Growth Factor beta; Valsartan

Endoglin is a membrane glycoprotein primarily expressed by the vascular endothelium and involved in cardiovascular diseases. Upon the proteolytic processing of the membrane-bound protein, a circulating form of endoglin (soluble endoglin, sEng) can be released, and high levels of sEng have been observed in several endothelial-related pathological conditions, where it appears to contribute to endothelial dysfunction. Preeclampsia is a multisystem disorder of high prevalence in pregnant women characterized by the onset of high blood pressure and associated with increased levels of sEng. Although a pathogenic role for sEng involving hypertension has been reported in several animal models of preeclampsia, the exact molecular mechanisms implicated remain to be identified. To search for sEng-induced mediators of hypertension, we analyzed the protein secretome of human endothelial cells in the presence of sEng. We found that sEng induces the expression of BMP4 in endothelial cells, as evidenced by their proteomic signature, gene transcript levels, and BMP4 promoter activity. A mouse model of preeclampsia with high sEng plasma levels (

Topics: Animals; Bone Morphogenetic Protein 4; Carrier Proteins; Endoglin; Endothelial Cells; Female; Humans; Hypertension; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pre-Eclampsia; Pregnancy; Proteomics; Transforming Growth Factor beta; Up-Regulation

Uremic cardiomyopathy, characterized by hypertension, cardiac hypertrophy, and fibrosis, is a complication of chronic kidney disease (CKD). Urea transporter (UT) inhibition increases the excretion of water and urea, but the effect on uremic cardiomyopathy has not been studied. We tested UT inhibition by dimethylthiourea (DMTU) in 5/6 nephrectomy mice. This treatment suppressed CKD-induced hypertension and cardiac hypertrophy. In CKD mice, cardiac fibrosis was associated with upregulation of UT and vimentin abundance. Inhibition of UT suppressed vimentin amount. Left ventricular mass index in DMTU-treated CKD was less compared with non-treated CKD mice as measured by echocardiography. Nephrectomy was performed in UT-A1/A3 knockout (UT-KO) to further confirm our finding. UT-A1/A3 deletion attenuates the CKD-induced increase in cardiac fibrosis and hypertension. The amount of α-smooth muscle actin and tgf-β were significantly less in UT-KO with CKD than WT/CKD mice. To study the possibility that UT inhibition could benefit heart, we measured the mRNA of renin and angiotensin-converting enzyme (ACE), and found both were sharply increased in CKD heart; DMTU treatment and UT-KO significantly abolished these increases. Conclusion: Inhibition of UT reduced hypertension, cardiac fibrosis, and improved heart function. These changes are accompanied by inhibition of renin and ACE.

Topics: Actins; Animals; Cardiomegaly; Cardiomyopathies; Fibrosis; Heart Ventricles; Hypertension; Kidney; Male; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Peptidyl-Dipeptidase A; Renal Insufficiency, Chronic; RNA, Messenger; Transforming Growth Factor beta; Urea; Urea Transporters

This study investigated the therapeutic efficacy of Bu-Shen-Jiang-Ya decoction (BSJYD) on hypertensive renal damage to determine whether it regulates the expression of transforming growth factor-β (TGF-β)/SMADs signaling pathways, thereby relieving renal fibrosis in Dahl salt-sensitive (SS) rats. Dahl SS rats on a high-sodium diet were prospectively treated with BSJYD (n = 12) or valsartan (n = 12) for 8 weeks. The blood pressure (BP) of these rats was measured and their kidneys were subjected to biochemical analysis, including serum creatinine (Scr) and blood urea nitrogen (BUN); hematoxylin and eosin staining; Masson trichrome staining; real-time polymerase chain reaction; and western blot analysis. The primary outcome was that BSJYD significantly reduced BP, debased BUN, and Scr and ameliorated renal pathological changes. As underlying therapeutic mechanisms, BSJYD reduces TGFβ1 and Smad2/3 expression and suppresses renal fibrosis, as suggested by the decreased expression of connective tissue growth factor(CTGF). These data suggest that BSJYD acts as an optimal therapeutic agent for hypertensive renal damage by inhibiting the TGF-β/SMADs signaling pathway.

Topics: Animals; Blood Pressure; Connective Tissue Growth Factor; Drugs, Chinese Herbal; Hypertension; Kidney; Kidney Diseases; Male; Medicine, Chinese Traditional; Rats; Rats, Inbred Dahl; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Background Elevated levels of an endogenous Na/K-ATPase inhibitor marinobufagenin accompany salt-sensitive hypertension and are implicated in cardiac fibrosis. Immunoneutralization of marinobufagenin reduces blood pressure in Dahl salt-sensitive (Dahl-S) rats. The effect of the anti-marinobufagenin monoclonal antibody on blood pressure, left ventricular (LV) and renal remodeling, and gene expression were investigated in hypertensive Dahl-S rats. Methods and Results Dahl-S rats were fed high NaCl (8%, HS; n=14) or low NaCl (0.1%, LS; n=14) diets for 8 weeks. Animals were administered control antibody (LS control antibody, LSC; HS control antibody, HSC; n=7 per group) or anti-marinobufagenin antibody once on week 7 of diet intervention (n=7 per group). Levels of marinobufagenin, LV, and kidney mRNAs and proteins implicated in profibrotic signaling were assessed. Systolic blood pressure was elevated (211±8 versus 133±3 mm Hg,

Topics: Animals; Blood Pressure; Blotting, Western; Bufanolides; Disease Models, Animal; Echocardiography; Enzyme Inhibitors; Gene Expression Regulation; Heart Ventricles; Hypertension; Male; Rats; Rats, Inbred Dahl; RNA; Transforming Growth Factor beta; Ventricular Remodeling

Obesity increases the risk of diabetes mellitus (DM) and hypertension. We aimed to analyze the serum levels of cytokines that have relevance to the pathologies including, interleukin-4 (IL-4), transforming growth factor-β (TGF-β), interferon-γ (IFN-γ), and IL-6 cytokines of overweight men with DM and/or hypertension.. The study collected serum from 164 men. The sample population contained, 54 overweight men without DM or hypertension (control [CTL] group), 36 men with both DM and hypertension (DH group), 20 men with DM but no hypertension (D group), and 54 had hypertension without DM (H).. The main results showed that the concentration of IFN-γ in the DH group was significantly higher than the D, H, and CTL groups, IL-6 in DH and D groups was significantly lower than the CTL group. The serum level of TGF-β and IL-4 cytokines did not show any significant differences across the four groups. Serum levels of IL-6 were also significantly lower in untreated patients in D group than controls and in DH when compared with H groups.. In conclusion, it appears that the proinflammatory and anti-inflammatory cytokines either play a significant role in the pathogenesis of hypertension and DM or serve as markers for these pathologies. Accordingly, increased serum levels of IFN-γ may participate in the pathogenesis of hypertension in the diabetic patients and decreased IL-6 is associated with type 2 DM.

Topics: Antihypertensive Agents; Diabetes Mellitus, Type 2; Humans; Hypertension; Hypoglycemic Agents; Interferon-gamma; Interleukin-4; Interleukin-6; Male; Middle Aged; Obesity; Transforming Growth Factor beta

The pathogenesis of aortic dissection (AD) is unclear. The aim of this study was to explore the relationship between osteopontin (OPN) and AD. Fifty AD patients were enrolled; 29 had hypertension with AD (H-AD) and 21 no hypertension with HD (NH-AD). Twenty-five healthy controls (NH-C) and 14 patients with hypertension (H-C) were also enrolled. Serum and aortic wall OPN levels were determined. Human vascular muscle cells (HVSMC) were stimulated by both low (1 μg/mL) and high (5 μg/mL) concentrations of OPN and cell proliferation as well as apoptosis was measured. Transforming growth factor-β (TGF-β), matrix metalloproteinase 1 (MMP-1), MMP-2, MMP-9, TIMP-1, and TIMP-2 gene expressions by HVSMC were measured and Akt, IκB, Smad1/5/8 and Erk1/2 signaling pathways were detected. Our results showed that AD patients demonstrated significantly higher levels of serum and local OPN expressions compared to healthy controls. In those with hypertension, the serum concentrations of OPN were increased compared to those without hypertension. In in vitro culture, a high dose of OPN stimulation promoted the proliferation of HVSMC but did not affect cell apoptosis. Both concentrations of OPN enhanced MMP-2 gene expression and its activity in HVSMC. Moreover, Akt and IκB signaling pathways were significantly activated after OPN stimulation while the Smad1/5/8 and Erk1/2 signaling pathways were not changed. The addition of an IκB inhibitor significantly abrogated MMP-2 gene expression. Our data show that OPN may participate in the pathogenesis of AD by the enhancement of MMP-2 expression.

Topics: Aorta; Aortic Dissection; Apoptosis; Cell Proliferation; Female; Gene Expression Profiling; Humans; Hypertension; I-kappa B Proteins; Male; Matrix Metalloproteinase 2; Myocytes, Smooth Muscle; Osteopontin; Proto-Oncogene Proteins c-akt; Signal Transduction; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta

Topics: Animals; Deep Learning; Disease Models, Animal; Endothelin-1; Endothelium; Epithelial-Mesenchymal Transition; Human Umbilical Vein Endothelial Cells; Humans; Hypertension; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Nitric Oxide Synthase Type III; RNA-Seq; Transfection; Transforming Growth Factor beta

The pharmacological blockade of galectin-3 (Gal-3), a β-galactoside-binding lectin, reduces renal impairment in acute kidney injury, hyperaldosteronism or nephropathy. We herein investigated the effects of pharmacological Gal-3 inhibition by modified citrus pectin (MCP) in renal damage in spontaneously hypertensive rats (SHRs).. Gal-3 inhibition did not modify blood pressure levels in 30-week-old SHR. Kidney weight was higher in SHR, with no effect of MCP treatment (100 mg/kg/day in the drinking water). Plasma creatinine and albuminuria were slightly but significantly increased in SHR and reduced by MCP, as well as plasma and urinary neutrophil gelatinase-associated lipocalin. In kidney from SHR, Gal-3 was upregulated, as well as the fibrotic markers (collagen type I, TGF-β and connective tissue growth factor) and tubulointerstitial fibrosis. MCP treatment reduced Gal-3 levels and fibrosis. The epithelial-mesenchymal transition (EMT) molecules (fibronectin, α-smooth muscle actin and β-catenin) were modified in SHR and normalized by Gal-3 inhibition. The inflammatory mediators (monocyte chemoattractant protein-1, osteopontin, cd68, cd80, cd44 and cd45) were elevated in SHR and attenuated by MCP. Renal damage markers (neutrophil gelatinase-associated lipocalin and kidney injury molecule-1) were augmented in SHR and improved by MCP. In renal epithelial normal rat kidney-52E cells, Gal-3 treatment induced EMT markers, whereas Gal-3 silencing attenuated EMT.. Gal-3 inhibition attenuated early renal damage in SHR as indicated by reduced albuminuria, improved renal function and decreased renal fibrosis, EMT and inflammation, independently of blood pressure levels. These data suggest that Gal-3 could be a potential therapeutic candidate for the prevention of early renal alterations in hypertension.

Topics: Actins; Acute Kidney Injury; Acute-Phase Proteins; Albuminuria; Animals; Antigens, CD; beta Catenin; Blood Pressure; Cell Line; Chemokine CCL2; Collagen Type I; Connective Tissue Growth Factor; Creatinine; Epithelial-Mesenchymal Transition; Fibronectins; Fibrosis; Galectin 3; Hypertension; Kidney; Kidney Diseases; Lipocalin-2; Lipocalins; Male; Organ Size; Osteopontin; Pectins; Proto-Oncogene Proteins; Rats; Rats, Inbred SHR; Transforming Growth Factor beta; Up-Regulation

The number of patients with adrenal aldosterone-producing adenomas (APAs) has gradually increased. However, even after adenoma resection, some patients still suffer from high systolic blood pressure (SBP), which is possibly due to great arterial remodeling. Moreover, mineralocorticoid receptors (MRs) were found to be expressed in vascular smooth muscle cells (VSMCs). This study aims to determine whether MR antagonism protects the aorta from aldosterone-induced aortic remolding. Male rats were subcutaneously implanted with an osmotic minipumps and randomly divided into four groups: control; aldosterone (1 μg/h); aldosterone plus a specific MR antagonist, eplerenone (100 mg/kg/day); and aldosterone plus a vasodilator, hydralazine (25 mg/kg/day). After 8 weeks of infusion, aortic smooth muscle cell proliferation and collagen deposition, as well as the MDM2 and TGF-β1 expression levels in the aorta, were examined. Model rats with APAs were successfully constructed. Compared with the control rats, the model rats exhibited (1) marked SBP elevation, (2) no significant alteration in aortic morphology, (3) increased VSMC proliferation and MDM2 expression in the aorta, and (4) enhanced total collagen and collagen III depositions in the aorta, accompanied with up-regulated expression of TGF-β1. These effects were significantly inhibited by co-administration with eplerenone but not with hydralazine. These findings suggested that specific MR antagonism protects the aorta from aldosterone-induced VSMC proliferation and collagen deposition.

Topics: ACTH-Secreting Pituitary Adenoma; Aldosterone; Animals; Antihypertensive Agents; Aorta; Cell Proliferation; Collagen; Disease Models, Animal; Eplerenone; Hydralazine; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Muscle, Smooth, Vascular; Proto-Oncogene Proteins c-mdm2; Random Allocation; Rats, Sprague-Dawley; Spironolactone; Transforming Growth Factor beta; Vascular Remodeling; Vasodilator Agents

The purpose of this study was to evaluate the effects of exercise training on renal fibrosis in hypertensive rats. Masson's trichrome staining and Western blotting were performed on the excised renal cortex from sixteen male spontaneously hypertensive rats (SHR), which were randomly divided into either a sedentary hypertensive group (SHR) or exercise hypertensive group (SHR-EX, running on an exercise treadmill for 60 min/day, 5 sessions/week, for 12 weeks), and from eight male Wistar-Kyoto rats which served as a sedentary normotensive group (WKY). The systolic blood pressure (SBP) and renal fibrosis in hypertensive rats improved after exercise training. The inflammatory-related protein levels of interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2), as well as the fibrotic-related protein levels of transforming growth factor-beta (TGF-β), phospho-Smad2/3 (p-Smad2/3), connective tissue growth factor (CTGF), matrix metalloproteinase-9 (MMP-9), and matrix metalloproteinase-2 (MMP-2) were decreased in the SHR-EX group when compared with the SHR group. Exercise training suppressed the hypertension-induced renal cortical inflammatory and fibrotic pathways in hypertensive rat models. These findings might indicate a new therapeutic effect for exercise training to prevent renal fibrosis in hypertensive nephropathy.

Topics: Animals; Connective Tissue Growth Factor; Cyclooxygenase 2; Exercise Therapy; Fibrosis; Gene Expression Regulation; Humans; Hypertension; Interleukin-6; Kidney Diseases; Matrix Metalloproteinase 9; Rats; Rats, Inbred SHR; Sedentary Behavior; Transforming Growth Factor beta

Topics: Animals; ErbB Receptors; Extracellular Matrix; Humans; Hypertension; Membrane Glycoproteins; Mice; Transcriptional Activation; Transforming Growth Factor beta; Transforming Growth Factors

Cardiovascular disease constitutes the leading cause of mortality in patients with chronic kidney disease (CKD) and end-stage renal disease. Despite increasing recognition of a close interplay between kidney dysfunction and cardiovascular disease, termed cardiorenal syndrome (CRS), the underlying mechanisms of CRS remain poorly understood. Here we report the development of pathological cardiac hypertrophy and fibrosis in early stage non-uremic CKD. Moderate kidney failure was induced three weeks after unilateral urinary obstruction (UUO) in mice. We observed pathological cardiac hypertrophy and increased fibrosis in UUO-induced CKD (UUO/CKD) animals. Further analysis indicated that this cardiac fibrosis was associated with increased expression of transforming growth factor β (TGF-β) along with significant upregulation of Smad 2/3 signaling in the heart. Moreover early treatment of UUO/CKD animals with an angiotensin-converting-enzyme inhibitor (ACE I), Enalapril, significantly attenuated cardiac fibrosis. Enalapril antagonized activation of the TGF-β signaling pathway in the UUO/CKD heart. In summary our study demonstrates the presence of pathological cardiac hypertrophy and fibrosis in mice early in UUO-induced CKD, in association with early activation of the TGF-β/Smad signaling pathway. We also demonstrate the beneficial effect of ACE I in alleviating this early fibrogenic process in the heart in UUO/CKD animals.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiomegaly; Enalapril; Fibrosis; Heart Ventricles; Hypertension; Male; Mice, Inbred C57BL; Organ Size; Renal Insufficiency, Chronic; Signal Transduction; Transforming Growth Factor beta; Up-Regulation; Ureteral Obstruction; Ventricular Remodeling

Endothelial dysfunction and arterial stiffening play major roles in cardiovascular diseases. The critical role for the miR-181 family in vascular inflammation has been documented. Here we tested whether the miR-181 family can influence the pathogenesis of hypertension and vascular stiffening.. qPCR data showed a significant decrease in miR-181b expression in the aorta of the older mice. Eight miR-181a1/b1-/- mice and wild types (C57BL6J:WT) were followed weekly for pulse wave velocity (PWV) and blood pressure measurements. After 20 weeks, the mice were tested for endothelial function and aortic modulus. There was a progressive increase in PWV and higher systolic blood pressure in miR-181a1/b1-/- mice compared with WTs. At 21 weeks, aortic modulus was significantly greater in the miR-181a1/b1-/- group, and serum TGF-β was found to be elevated at this time. A luciferase reporter assay confirmed miR-181b targets TGF-βi (TGF-β induced) in the aortic VSMCs. In contrast, wire myography revealed unaltered endothelial function along with higher nitric oxide production in the miR-181a1/b1-/- group. Cultured VECs and VSMCs from the mouse aorta showed more secreted TGF-β in VSMCs of the miR-181a1/b1-/- group; whereas, no change was observed from VECs. Circulating levels of angiotensin II were similar in both groups. Treatment with losartan (0.6 g/L) prevented the increase in PWV, blood pressure, and vascular stiffness in miR-181a1/b1-/- mice. Immunohistochemistry and western blot for p-SMAD2/3 validated the inhibitory effect of losartan on TGF-β signaling in miR-181a1/b1-/- mice.. Decreased miR-181b with aging plays a critical role in ECM remodeling by removing the brake on the TGF-β, pSMAD2/3 pathway.

Topics: Aging; Angiotensin II; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Cardiovascular Diseases; Endothelial Cells; Extracellular Matrix; Hypertension; Losartan; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; Nitric Oxide; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta; Vascular Stiffness

A soluble form of endoglin (sEng) released into the circulation was suggested to be a direct inducer of endothelial dysfunction, inflammation and contributed to the development of hypertension by interfering with TGF-β signaling in cardiovascular pathologies. In the present study, we assessed the hypothesis that high sEng level-induced hypertension via a possible sEng interference with TGF-β signaling pathways may result in inflammatory, structural or fibrotic changes in hearts of Sol-Eng+ mice (mice with high levels of soluble endoglin) fed either chow or high-fat diet. Female Sol-Eng+ mice and their age matched littermates with low plasma levels of sEng were fed either chow or high-fat diet (HFD). Heart samples were subsequently analyzed by histology, qRT-PCR and Western blot analysis. In this study, no differences in myocardial morphology/hypertrophy and possible fibrotic changes between Sol-Eng+ mice and control mice were detected on both chow and HFD. The presence of sEng did not significantly affect the expression of selected members of TGF-β signaling (membrane endoglin, TGFβRII, ALK-5, ALK-1, Id-1, PAI-1 and activated Smad proteins-pSmad 1,5 and pSmad 2,3), inflammation, heart remodeling (PDGFb, Col1A1) and endothelial dysfunction (VCAM-1, ICAM-1) in the hearts of Sol-Eng+ mice compared to control mice on both chow and high-fat diet. High levels of soluble endoglin did not affect microscopic structure (profibrotic and degenerative cardiomyocyte changes), and specific parts of TGF-β signaling, endothelial function and inflammation in the heart of Sol-Eng+ mice fed both chow diet or HFD. However, we cannot rule out a possibility that a long-term chronic exposure (9 months and more) to soluble endoglin alone or combined with other cardiovascular risk factors may contribute to alterations of heart function and structure in Sol-Eng+ mice, which is the topic in our lab in ongoing experiments.

Topics: Animals; Blotting, Western; Cardiomyopathy, Hypertrophic; Disease Models, Animal; Endoglin; Female; Gene Expression Profiling; Gene Expression Regulation; Heart; Hypertension; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardium; Oxidative Stress; Real-Time Polymerase Chain Reaction; RNA; Signal Transduction; Transforming Growth Factor beta

The aim of the study was to compare the effects of chronic oral treatment with carvedilol or amlodipine on blood pressure, blood pressure variability and target organ damage in N-nitro-l-arginine methyl ester (L-NAME) hypertensive rats. Wistar rats were treated with L-NAME administered in the drinking water for 8 weeks together with oral administration of carvedilol 30 mg/kg (n = 6), amlodipine 10 mg/kg (n = 6), or vehicle (n = 6). At the end of the treatment, echocardiographic evaluation, blood pressure, and short-term variability measurements were performed. Left ventricular and thoracic aortas were removed to assess activity of metalloproteinase 2 and 9 and expression levels of transforming growth factor β, tumor necrosis factor α, and interleukin 6. Histological samples were prepared from both tissues. Carvedilol and amlodipine induced a comparable reduction of systolic and mean arterial pressure and its short-term variability in L-NAME rats. The expression of transforming growth factor β, tumor necrosis factor α, and interleukin 6 decreased in both organs after carvedilol or amlodipine treatment and the activity of metalloproteinase was reduced in aortic tissue. Treatment with carvedilol or amlodipine completely prevented left ventricular collagen deposition and morphometric alterations in aorta. Oral chronic treatment with carvedilol or amlodipine significantly attenuates blood pressure variability and reduces target organ damage and biomarkers of tissue fibrosis and inflammation in L-NAME hypertensive rats.

Topics: Amlodipine; Animals; Antihypertensive Agents; Aorta; Biomarkers; Blood Pressure; Blood Pressure Determination; Carbazoles; Carvedilol; Collagen; Disease Models, Animal; Fibrosis; Heart Ventricles; Humans; Hypertension; Interleukin-6; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; NG-Nitroarginine Methyl Ester; Propanolamines; Rats; Rats, Wistar; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Female spontaneously hypertensive rats (SHR) have more renal regulatory T cells (Tregs) than males, and greater levels of Tregs in female SHR are dependent on blood pressure (BP). However, the molecular mechanism responsible for greater Tregs in female SHR is unknown. Transforming growth factor (TGF)-β is a pleiotropic cytokine critical in the differentiation of naïve T cells into Tregs, and female SHR have higher TGF-β excretion than male SHR. The goals of the current study were to test the hypotheses that

Topics: Animals; Antihypertensive Agents; Female; Hypertension; Kidney; Male; Rats, Inbred SHR; Sex Characteristics; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Angiotensin-converting enzyme-2 (ACE2) is downregulated in hypertensive nephropathy. The present study investigated the mechanisms whereby loss of ACE2 promoted angiotensin II-induced hypertensive nephropathy in ACE2 gene knockout mice. We found that compared with wild-type animals, mice lacking ACE2 developed much more severe hypertensive nephropathy in response to chronic angiotensin II infusion, including higher levels of blood pressure, urinary protein excretion, serum creatinine, and progressive renal fibrosis and inflammation. Mechanistic studies revealed that worsening kidney injury in ACE2 knockout mice was associated with an increase in Smurf2 (Smad-specific E3 ubiquitin protein ligase 2), a decrease in renal Smad7, and marked activation of TGF-β (transforming growth factor β)/Smad3 and NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling, suggesting that Smurf2-dependent Smad7 ubiquitin degradation may be a key mechanism whereby loss of ACE2 promotes angiotensin II-induced TGF-β/Smad3 and NF-κB-mediated hypertensive nephropathy. This was validated by restoring Smad7 locally in the kidneys of ACE2 knockout mice to block angiotensin II-induced TGF-β/Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation. Moreover, we found that angiotensin II could induce microRNA-21 in the mouse kidney and in cultured mesangial cells via a Smad3-dependent mechanism, which was enhanced by deleting ACE2 but inhibited by overexpressing renal Smad7. In conclusion, loss of ACE2 promotes angiotensin II-induced renal injury by targeting Smad7 for degradation via a Smurf2-dependent mechanism. Overexpression of renal Smad7 protects against hypertensive nephropathy by inactivating angiotensin II-induced TGF-β/Smad3 and NF-κB pathways and by targeting the Smad3-dependent microRNA-21 axis.

Topics: Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Down-Regulation; Fibrosis; Hypertension; Hypertension, Renal; Inflammation; Kidney; Mice; Mice, Knockout; Nephritis; NF-kappa B; Peptidyl-Dipeptidase A; Signal Transduction; Smad1 Protein; Smad7 Protein; Transforming Growth Factor beta; Ubiquitin

Besides environmental risk factors, genetic factors play a crucial role in the pathogenesis of primary hypertension. The current study is to unravel whether hypertensive phenotypes vary in mice with different genetic background.. Hypertension was induced in C57BL/6J (B6), DBA/2J (D2), and 25 BXD strains by administrating angiotensin (Ang)II (2.5 mg/kg/day infused by osmotic minipump) for 4 weeks. Systolic blood pressure was monitored before (baseline) and after 4 weeks of AngII treatment by tail cuff. Cardiac and renal fibrosis was evaluated by picrosirius red staining and collagen volume fraction (CVF) was quantitated using imaging analyzing system; cardiac transforming growth factor (TGF)-β gene expression was monitored by RT-PCR, and inflammatory response was detected by immunohistochemical ED-1 staining.. AngII infusion caused hypertension in all strains. However, blood pressure elevation was more evident in the D2 strain than the B6 group, while it was widely variable among BXD strains. Furthermore, chronic AngII treatment lead to development of hypertensive cardiac and renal diseases. Cardiac and renal CVF levels in the D2 strain was significantly higher than the B6 cohort, whereas these varied vastly across BXD strains. Moreover, cardiac TGF-β mRNA levels were markedly diverse among various mouse strains.. Our study unequivocally demonstrates that in response to AngII, BXDs with different genetic background expressed hypertension phenotypes with varied degree in severity. It implicates that genomics contribute to pathogenesis of primary hypertension. Building upon the genotype and hypertensive phenotypes, the BXD cohort can be further exploited experimentally to identify genes that influence blood pressure.

Topics: Angiotensin II; Animals; Blood Pressure; Fibrosis; Heart Diseases; Hypertension; Inflammation; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Inbred Strains; Phenotype; Species Specificity; Transforming Growth Factor beta; Vasoconstrictor Agents

Hypothalamic inflammation was recently found to mediate obesity-related hypertension, but the responsible upstream mediators remain unexplored. In this study, we show that dietary obesity is associated with extracellular release of mitochondrial DNA (mtDNA) into the cerebrospinal fluid and that central delivery of mtDNA mimics transforming growth factor-β (TGFβ) excess to activate downstream signaling pathways. Physiological study reveals that central administration of mtDNA or TGFβ is sufficient to cause hypertension in mice. Knockout of the TGFβ receptor in proopiomelanocortin neurons counteracts the hypertensive effect of not only TGFβ but also mtDNA excess, while the hypertensive action of central mtDNA can be blocked pharmacologically by a TGFβ receptor antagonist or genetically by TGFβ receptor knockout. Finally, we confirm that obesity-induced hypertension can be reversed through central treatment with TGFβ receptor antagonist. In conclusion, circulating mtDNA in the brain employs neural TGFβ pathway to mediate a central inflammatory mechanism of obesity-related hypertension.

Topics: Animals; Benzamides; Blood Pressure; Blotting, Western; Diet, High-Fat; Dioxoles; DNA, Mitochondrial; Hypertension; Hypothalamus; Male; Mice; Mice, Knockout; Neurons; Obesity; Pro-Opiomelanocortin; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Third Ventricle; Transforming Growth Factor beta; Transforming Growth Factor beta1

Hypertensive ventricular remodeling is a common cause of heart failure. However, the molecular mechanisms regulating ventricular remodeling remain poorly understood.. We used a discovery-driven/nonbiased approach to identify increased activating transcription factor 3 (ATF3) expression in hypertensive heart. We used loss/gain of function approaches to understand the role of ATF3 in heart failure. We also examined the mechanisms through transcriptome, chromatin immunoprecipitation sequencing analysis, and in vivo and in vitro experiments.. ATF3 expression increased in murine hypertensive heart and human hypertrophic heart. Cardiac fibroblast cells are the primary cell type expressing high ATF3 levels in response to hypertensive stimuli. ATF3 knockout (ATF3KO) markedly exaggerated hypertensive ventricular remodeling, a state rescued by lentivirus-mediated/miRNA-aided cardiac fibroblast-selective ATF3 overexpression. Conversely, conditional cardiac fibroblast cell-specific ATF3 transgenic overexpression significantly ameliorated ventricular remodeling and heart failure. We identified Map2K3 as a novel ATF3 target. ATF3 binds with the Map2K3 promoter, recruiting HDAC1, resulting in Map2K3 gene-associated histone deacetylation, thereby inhibiting Map2K3 expression. Genetic Map2K3 knockdown rescued the profibrotic/hypertrophic phenotype in ATF3KO cells. Last, we demonstrated that p38 is the downstream molecule of Map2K3 mediating the profibrotic/hypertrophic effects in ATF3KO animals. Inhibition of p38 signaling reduced transforming growth factor-β signaling-related profibrotic and hypertrophic gene expression, and blocked exaggerated cardiac remodeling in ATF3KO cells.. Our study provides the first evidence that ATF3 upregulation in cardiac fibroblasts in response to hypertensive stimuli protects the heart by suppressing Map2K3 expression and subsequent p38-transforming growth factor-β signaling. These results suggest that positive modulation of cardiac fibroblast ATF3 may represent a novel therapeutic approach against hypertensive cardiac remodeling.

Topics: Acetylation; Activating Transcription Factor 3; Angiotensin II; Animals; Binding Sites; Cells, Cultured; Disease Models, Animal; Fibroblasts; Fibrosis; Genetic Predisposition to Disease; Heart Failure; Histone Deacetylase 1; Histones; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; MAP Kinase Kinase 3; Mice, Knockout; Myocardium; p38 Mitogen-Activated Protein Kinases; Phenotype; Promoter Regions, Genetic; Protein Kinase Inhibitors; Signal Transduction; Time Factors; Transforming Growth Factor beta; Ventricular Function, Left; Ventricular Remodeling

To evaluate the improving effects of specifically overexpressed connective tissue growth factor (CTGF) in cardiomyocytes on mice with hypertension induced by angiotensin II (AngII) perfusion, 24 transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) were divided into two equal groups that were perfused with acetic acid and AngII, respectively, for 7 days. Another 24 cage-control wild-type C57BL/6 mice (NLC) were divided and treated identically. Blood pressure was detected by caudal artery cannulation. Cardiac structural and functional changes were observed by echocardiography. Cardiac fibrosis was detected by Masson staining. After AngII perfusion, blood pressures of NLC and Tg-CTGF mice, especially those of the formers, significantly increased. Compared with NLC + AngII group, Tg-CTGF + AngII group had significantly lower left ventricular posterior wall thickness at end-diastole and left ventricular posterior wall thickness at end-systole as well as significantly higher left ventricular end-systolic diameter and left ventricular end-diastolic diameter (P < 0.05). Reverse transcription-polymerase chain reaction (RT-PCR) showed that Tg-CTGF + AngII group had significantly lower collagen I, α-SMA, and TGF-β mRNA expressions in cardiac tissues (P < 0.05). Tg-CTGF can protect AngII-induced cardiac remodeling of mice with hypertension by mitigating inflammatory response. CTGF may be a therapy target for hypertension-induced myocardial fibrosis, but the detailed mechanism still needs in-depth studies.

Topics: Actins; Angiotensin II; Animals; Blood Pressure; Cardiomegaly; Collagen Type I; Connective Tissue Growth Factor; Echocardiography; Fibrosis; Heart; Heart Ventricles; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardium; Myocytes, Cardiac; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Vasoconstrictor Agents; Ventricular Remodeling

Xue-Fu-Zhu-Yu decoction (XFZYD), Tian-Ma-Gou-Teng-Yin (TMGTY) and Wen-Dan decoction (WDD) are Chinese herbal formulas used to treat hypertension and cardiovascular diseases in traditional Chinese medicine (TCM). The goal of our study is to determine if XFZYD, TMGTY or WDD treatment ameliorated myocardial fibrosis in spontaneously hypertensive rats (SHRs) and to identify the mechanisms underlying any beneficial effects observed during the courses of the investigation.. Forty-five 12-week-old male spontaneously hypertensive rats and five age-matched male Wistar-Kyoto control rats were studied for 16 weeks. Each day 6 g∙kg(-1) or 12 g∙kg(-1) of XFZYD, TMGTY or WDD was orally administered at the indicated dose, and the systolic blood pressure (SBP) of all rats was measured using the tail-cuff method. Collagen levels were measured via hydroxyproline content assays and histological examination. Transforming growth factor beta-1 (TGF-β1) protein levels were determined via immunhistochemical and Western blot analysis. TGF-β1 mRNA levels were assessed using real-time reverse transcription polymerase chain reaction.. Systolic blood pressure was unaffected, but collagen and TGF-β1 levels in SHRs treated with captopril and XFZYD (12 g∙kg(-1)) were significantly reduced when compared with untreated control SHRs. Administration of 12 g∙kg(-1) XFZYD increased myocardial cell protection and decreased TGF-β1 mRNA and protein expression when compared with the other SHR treatment groups.. XFZYD treatment demonstrated a superior ability to reverse myocardial fibrosis when compared with WDD or TMGTY treatment in SHRs. XFZYD also decreased TGF-β1 mRNA and protein expression, suggesting that the TGF-β1 signaling pathway plays a role in the therapeutic effects of XFZYD treatment.

Topics: Animals; Blood Pressure; Collagen; Disease Models, Animal; Drugs, Chinese Herbal; Endomyocardial Fibrosis; Hydroxyproline; Hypertension; Male; Rats; Rats, Inbred WKY; Transforming Growth Factor beta

Progressive fibrosis in chronic kidney disease (CKD) is the well-recognized cause leading to the progressive loss of renal function. Emerging evidence indicated a pathogenic role of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome in mediating kidney injury. However, the role of NLRP3 in the remnant kidney disease model is still undefined. The present study was undertaken to evaluate the function of NLRP3 in modulating renal fibrosis in a CKD model of 5/6 nephrectomy (5/6 Nx) and the potential involvement of mitochondrial dysfunction in the pathogenesis. Employing NLRP3(+/+) and NLRP3(-/-) mice with or without 5/6 Nx, we examined renal fibrotic response and mitochondrial function. Strikingly, tubulointerstitial fibrosis was remarkably attenuated in NLRP3(-/-) mice as evidenced by the blockade of extracellular matrix deposition. Meanwhile, renal tubular cells in NLRP3(-/-) mice maintained better mitochondrial morphology and higher mitochondrial DNA copy number, indicating an amelioration of mitochondrial abnormality. Moreover, NLRP3 deletion also blunted the severity of proteinuria and CKD-related hypertension. To further evaluate the direct role of NLRP3 in triggering fibrogenesis, mouse proximal tubular cells (PTCs) were subjected to transforming growth factor β1 (TGF-β1), and the cellular phenotypic changes were detected. As expected, TGF-β1-induced alterations of PTC phenotype were abolished by NLRP3 small interfering RNA, in line with a protection of mitochondrial function. Taken together, NLRP3 deletion protected against renal fibrosis in the 5/6 Nx disease model, possibly via inhibiting mitochondrial dysfunction.

Topics: Animals; Cells, Cultured; Hypertension; Mice; Mice, Inbred C57BL; Mitochondrial Diseases; Nephrectomy; Nephrosclerosis; NLR Family, Pyrin Domain-Containing 3 Protein; Proteinuria; Renal Insufficiency, Chronic; RNA, Small Interfering; Transforming Growth Factor beta

Chronic hypertension is the most critical risk factor for cardiovascular disease, heart failure, and stroke.. Here we show that wild-type mice infused with angiotensin II develop hypertension, cardiac hypertrophy, perivascular fibrosis, and endothelial dysfunction with enhanced stromal interaction molecule 1 (STIM1) expression in heart and vessels. All these pathologies were significantly blunted in mice lacking STIM1 specifically in smooth muscle (Stim1(SMC-/-)). Mechanistically, STIM1 upregulation during angiotensin II-induced hypertension was associated with enhanced endoplasmic reticulum stress, and smooth muscle STIM1 was required for endoplasmic reticulum stress-induced vascular dysfunction through transforming growth factor-β and nicotinamide adenine dinucleotide phosphate oxidase-dependent pathways. Accordingly, knockout mice for the endoplasmic reticulum stress proapoptotic transcriptional factor, CCAAT-enhancer-binding protein homologous protein (CHOP(-/-)), were resistant to hypertension-induced cardiovascular pathologies. Wild-type mice infused with angiotensin II, but not Stim1(SMC-/-) or CHOP(-/-) mice showed elevated vascular nicotinamide adenine dinucleotide phosphate oxidase activity and reduced phosphorylated endothelial nitric oxide synthase, cGMP, and nitrite levels.. Thus, smooth muscle STIM1 plays a crucial role in the development of hypertension and associated cardiovascular pathologies and represents a promising target for cardiovascular therapy.

Topics: Angiotensin II; Animals; Blood Pressure; Cardiomegaly; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; Fibrosis; Genetic Predisposition to Disease; Hypertension; Male; Mice, Knockout; Muscle, Smooth, Vascular; Myocardium; NADPH Oxidases; Nitric Oxide Synthase Type III; Nitrites; Phenotype; Phosphorylation; Reactive Oxygen Species; Signal Transduction; Stromal Interaction Molecule 1; Time Factors; Transcription Factor CHOP; Transforming Growth Factor beta; Vasodilation; Vasodilator Agents

Coronary artery disease (CAD) and hypertension are the main reasons of ischemic heart diseases (IHDs). Cytokines as the small glycoproteins are the main arm of immune system and manipulate all of the cardiovascular diseases. The aim of the current study was to examine the effects of treatment of hypertension and CAD on serum levels of IL-6, IL-8, TGF-β and TNF-α.. This interventional study was performed on the patients with hypertension without CAD (group 1), hypertension and CAD (group 2), CAD but not hypertension (group 3) and without hypertension and CAD as controls (group 4). The patients received routine treatment for hypertension and CAD. Serum levels of IL-6, IL-8, TGF-β and TNF-α were analyzed in the groups treated with various drugs, using ELISA technique.. With regard to the medications, Atorvastatin, Losartan and Captopril were administered more in patients (groups 1, 2 and 3) than the patients without hypertension and CAD. The results revealed that serum levels of TGF-β and IL-6 were significantly increased and decreased, respectively, in the groups 1, 2 and 3 when compared to group 4. Serum levels of TGF-β were also increased in females in comparison to males in the group 4.. According to the results it seems that Atorvastatin, Losartan and Captopril have reduced inflammation in in vivo conditions via downregulation of IL-6 and upregulation of TGF-β.

Topics: Antihypertensive Agents; Atorvastatin; Captopril; Coronary Artery Disease; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Inflammation; Interleukin-6; Interleukin-8; Iran; Losartan; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Up-Regulation

The effect of the heptapeptide hormone Ang-(1-7) on microvascular fibrosis in rats with Ang II-induced hypertension was investigated, since vascular fibrosis/remodeling plays a prominent role in hypertension-induced end-organ damage and Ang-(1-7) inhibits vascular growth and fibrosis.. Fibrosis of cremaster microvessels was studied in male Lewis rats infused with Ang II and/or Ang-(1-7).. Ang II elevated systolic blood pressure by approximately 40 mmHg, while blood pressure was not changed by Ang-(1-7). Ang II increased perivascular fibrosis surrounding 20-50 μm arterioles as well as interstitial fibrosis; coadministration of Ang-(1-7) prevented the increases in fibrosis. The fibrotic factor CTGF and phospho-Smad 2/3, which upregulates CTGF, were increased by Ang II; this effect was prevented by coadministration of Ang-(1-7). Although TGF-β phosphorylates Smad 2/3, TGF-β was no different among treatment groups. In contrast, Ang II increased the MAP kinase phospho-ERK1/2, which also phosphorylates Smad; p-ERK was reduced by Ang-(1-7). Ang-(1-7), in the presence or absence of Ang II, upregulated the MAP kinase phosphatase DUSP1.. These results suggest that Ang-(1-7) increases DUSP1 to reduce MAP kinase/Smad/CTGF signaling and decrease fibrosis in resistance arterioles, to attenuate end-organ damage associated with chronic hypertension.

Topics: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Arterioles; Blood Pressure; Chronic Disease; Connective Tissue Growth Factor; Dual Specificity Phosphatase 1; Fibrosis; Hypertension; Male; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 3; Muscle, Skeletal; Peptide Fragments; Phosphorylation; Rats; Rats, Inbred Lew; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta; Vasoconstrictor Agents

We assessed the association between 5 well-defined polymorphisms of the transforming growth factor-β1 (TGFB1) gene and coronary artery disease (CAD) among patients with hypertension from northeast China. All study participants were classified into patients with CAD (n = 679) and controls (n = 686) according to angiographic results. Genotyping was carried out with the ligase detection reaction method. In single-locus analysis, only genotypes of rs1800469 differed significantly between patients with CAD and controls (P = .001); patients carrying the mutant allele of rs1800469 exhibited a 73% increased risk of CAD (P < .001). Haplotype analysis indicated that haplotype A-T-T-C-C (alleles in the order of rs1800468, rs1800469, rs1800470, rs1800471, and rs1800472) was associated with a 1.49-fold increased risk (P = .003). Interaction analysis identified an overall best 3-locus model including rs1800469, rs1800468, and rs1800471 (P = .003). Taken together, we identified a synergistic interaction between TGFB1 gene multiple polymorphisms that entailed greater risk of CAD in Chinese patients.

Topics: Aged; Alleles; Biomarkers; Case-Control Studies; China; Coronary Angiography; Coronary Artery Disease; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Hypertension; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Transforming Growth Factor beta

The study was designed to explore the role and possible mechanisms of hydrogen sulfide (H2S) in the regulation of myocardial collagen remodeling in spontaneously hypertensive rats (SHRs). We treated nine-week-old male SHRs and age- and sex-matched Wistar-Kyoto rats (WKYs) with NaHS (90 μmol/kg(-1)·day(-1)) for 9 wks. At 18 wks, plasma H2S, tail arterial pressure, morphology of the heart, myocardial ultrastructure and collagen volume fraction (CVF), myocardial expressions of collagen I and III protein and procollagen I and III mRNA, transforming growth factor-β1 (TGF-β1), TGF-β type I receptor (TβR-I), type II receptor (TβR-II), p-Smad2 and 3, matrix metalloproteinase (MMP)-13 and tissue inhibitors of MMP (TIMP)-1 proteins were determined. TGF-β1-stimulated cultured cardiac fibroblasts (CFs) were used to further study the mechanisms. The results showed that compared with WKYs, SHRs showed a reduced plasma H2S, elevated tail artery pressure and increased myocardial collagen, TGF-β1, TβR-II, p-Smad2 and p-Smad3 expressions. However, NaHS markedly decreased tail artery pressure and inhibited myocardial collagen, TGF-β1, TβR-II, p-Smad2 and p-Smad3 protein expressions, but H2S had no effect on the expressions of MMP-13 and TIMP-1. Hydralazine reduced blood pressure but had no effect on myocardial collagen, MMP-13 and TIMP-1 expressions and TGF-β1/Smad signaling pathway. H2S prevented activation of the TGF-β1/Smad signaling pathway and abnormal collagen synthesis in CFs. In conclusion, the results suggested that H2S could prevent myocardial collagen remodeling in SHR. The mechanism might be associated with inhibition of collagen synthesis via TGF-β1/Smad signaling pathway.

Topics: Animals; Arterial Pressure; Cells, Cultured; Collagen Type I; Collagen Type III; Fibroblasts; Hydrogen Sulfide; Hypertension; Male; Microscopy, Electron, Transmission; Myocardium; Protein Serine-Threonine Kinases; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad2 Protein; Smad3 Protein; Sulfides; Transforming Growth Factor beta

It is well known that biological tissues adapt their properties because of different mechanical and chemical stimuli. The goal of this work is to study the collagen turnover in the arterial tissue of hypertensive patients through a coupled computational mechano-chemical model. Although it has been widely studied experimentally, computational models dealing with the mechano-chemical approach are not. The present approach can be extended easily to study other aspects of bone remodeling or collagen degradation in heart diseases. The model can be divided into three different stages. First, we study the smooth muscle cell synthesis of different biological substances due to over-stretching during hypertension. Next, we study the mass-transport of these substances along the arterial wall. The last step is to compute the turnover of collagen based on the amount of these substances in the arterial wall which interact with each other to modify the turnover rate of collagen. We simulate this process in a finite element model of a real human carotid artery. The final results show the well-known stiffening of the arterial wall due to the increase in the collagen content.

Topics: Carotid Arteries; Collagen; Computer Simulation; Fibroblasts; Finite Element Analysis; Humans; Hypertension; Matrix Metalloproteinase 1; Models, Cardiovascular; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

Esculetin (6, 7- dihydroxycoumarin) was found to be protective against hepatic and renal damage associated with Streptozotocin (STZ) induced type 1 diabetes, because of its radical scavenging property. However, there are no reports regarding its effect on vascular dysfunction under hyperinsulinemic and hyperglycemic conditions. Hence, the present study aimed to investigate the effect of esculetin on vascular dysfunction under these conditions. Non-genetic model of hyperinsulinemia and hyperglycemia were developed by high fat diet (HFD) feeding and HFD + Streptozotocin (STZ, 35 mg/kg, I.P) treatment in Wistar rats, respectively. Esculetin was administered at 50 and 100 mg/kg/day (P.O, 2 weeks) doses and biochemical, vascular reactivity and immunohistochemical experiments were performed to assess the effect of esculetin on vascular dysfunctions. Esculetin treatment significantly attenuates metabolic perturbations, alleviates insulin levels in hyperinsulinemic condition. Thoracic aorta of hyperinsulinemic and hyperglycemic rats showed hyper-responsiveness to Ang II mediated contraction and impaired acetylcholine mediated relaxation, and esculetin attenuates alterations in vascular reactivity to Ang II and acetylcholine challenges. In addition, immunohistochemical evaluations revealed that esculetin prevents increase in AT1R, AT2R, Keap1, TGF-β, and decrease in ACE2 expression in aorta of hyperinsulinemic and hyperglycemic rats.

Topics: Acetylcholine; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Antioxidants; Aorta; Blood Pressure; Diabetes Mellitus, Experimental; Hyperglycemia; Hyperinsulinism; Hypertension; Male; Peptidyl-Dipeptidase A; Rats, Wistar; Transforming Growth Factor beta; Umbelliferones

We assessed the predictive ability of selected biomarkers using N-terminal pro-brain natriuretic peptide (NT-proBNP) as the benchmark and tried to establish a multi-biomarker approach to heart failure (HF) in hypertensive patients. In 120 hypertensive patients with or without overt heart failure, the incremental predictive value of the following biomarkers was investigated: Collagen III N-terminal propeptide (PIIINP), cystatin C (CysC), lipocalin-2/NGAL, syndecan-4, tumor necrosis factor-α (TNF-α), interleukin 1 receptor type I (IL1R1), galectin-3, cardiotrophin-1 (CT-1), transforming growth factor β (TGF-β) and N-terminal pro-brain natriuretic peptide (NT-proBNP). The highest discriminative value for HF was observed for NT-proBNP (area under the receiver operating characteristic curve (AUC)=0.873) and TGF-β (AUC=0.878). On the basis of ROC curve analysis we found that CT-1>152 pg/mL, TGF-β<7.7 ng/mL, syndecan>2.3 ng/mL, NT-proBNP>332.5 pg/mL, CysC>1 mg/L and NGAL>39.9 ng/mL were significant predictors of overt HF. There was only a small improvement in predictive ability of the multi-biomarker panel including the four biomarkers with the best performance in the detection of HF-NT-proBNP, TGF-β, CT-1, CysC-compared to the panel with NT-proBNP, TGF-β and CT-1 only. Biomarkers with different pathophysiological backgrounds (NT-proBNP, TGF-β, CT-1, CysC) give additive prognostic value for incident HF in hypertensive patients compared to NT-proBNP alone.

Topics: Acute-Phase Proteins; Aged; Biomarkers; Cystatin C; Cytokines; Female; Galectin 3; Heart Failure; Humans; Hypertension; Lipocalin-2; Lipocalins; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Procollagen; Protein Precursors; Proto-Oncogene Proteins; Receptors, Interleukin-1 Type I; Syndecan-4; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Clinical hypertension is associated with raised serum IgG antibodies. However, whether antibodies are causative agents in hypertension remains unknown. We investigated whether hypertension in mice is associated with B-cell activation and IgG production and moreover whether B-cell/IgG deficiency affords protection against hypertension and vascular remodeling. Angiotensin II (Ang II) infusion (0.7 mg/kg per day; 28 days) was associated with (1) a 25% increase in the proportion of splenic B cells expressing the activation marker CD86, (2) an 80% increase in splenic plasma cell numbers, (3) a 500% increase in circulating IgG, and (4) marked IgG accumulation in the aortic adventitia. In B-cell-activating factor receptor-deficient (BAFF-R(-/-)) mice, which lack mature B cells, there was no evidence of Ang II-induced increases in serum IgG. Furthermore, the hypertensive response to Ang II was attenuated in BAFF-R(-/-) (Δ30±4 mm Hg) relative to wild-type (Δ41±5 mm Hg) mice, and this response was rescued by B-cell transfer. BAFF-R(-/-) mice displayed reduced IgG accumulation in the aorta, which was associated with 80% fewer aortic macrophages and a 70% reduction in transforming growth factor-β expression. BAFF-R(-/-) mice were also protected from Ang II-induced collagen deposition and aortic stiffening (assessed by pulse wave velocity analysis). Finally, like BAFF-R deficiency, pharmacological depletion of B cells with an anti-CD20 antibody attenuated Ang II-induced hypertension by ≈35%. Hence, these studies demonstrate that B cells/IgGs are crucial for the development of Ang II-induced hypertension and vessel remodeling in mice. Thus, B-cell-targeted therapies-currently used for autoimmune diseases-may hold promise as future treatments for hypertension.

Topics: Adoptive Transfer; Angiotensin II; Animals; Antibodies, Anti-Idiotypic; Antigens, CD20; B-Cell Activation Factor Receptor; B-Lymphocytes; Cell Proliferation; Disease Models, Animal; Hypertension; Immunoglobulin G; Mice; Mice, Knockout; Spleen; Transforming Growth Factor beta; Vascular Stiffness

The functional crosstalk between angiotensin II (Ang II) and tumor necrosis factor (TNF)-α has been shown to cause adverse left ventricular remodeling and hypertrophy in hypertension. Previous studies from our lab showed that mice lacking TNF-α (TNF-α-/-) have attenuated hypertensive response to Ang II; however, the signaling mechanisms involved are not known. In this study, we investigated the signaling pathways involved in the Ang II and TNF-α interaction. Chronic Ang II infusion (1 μg/kg/min, 14 days) significantly increased cardiac collagen I, collagen III, CTGF and TGF-β mRNA and protein expression in wild-type (WT) mice, whereas these changes were decreased in TNF-α-/- mice. TNF-α-/- mice with Ang II infusion showed reduced myocardial perivascular and interstitial fibrosis compared to WT mice with Ang II infusion. In WT mice, Ang II infusion increased reactive oxygen species formation and the expression of NADPH oxidase subunits, indicating increased oxidative stress, but not in TNF-α-/- mice. In addition, treatment with etanercept (8 mg/kg, every 3 days) for two weeks blunted the Ang II-induced hypertension (133 ± 4 vs 154 ± 3 mmHg, p<0.05) and cardiac hypertrophy (heart weight to body weight ratio, 4.8 ± 0.2 vs 5.6 ± 0.3, p<0.05) in WT mice. Furthermore, Ang II-induced activation of NF-κB, p38 MAPK, and JNK were reduced in both TNF-α-/- mice and mice treated with etanercept. Together, these findings indicate that TNF-α contributes to Ang II-induced hypertension and adverse cardiac remodeling, and that these effects are associated with changes in the oxidative stress dependent MAPK/TGF-β/NF-κB pathway. These results may provide new insight into the mechanisms of Ang II and TNF-α interaction.

Topics: Angiotensin II; Animals; Blood Pressure; Cardiomegaly; Collagen Type I; Collagen Type III; Connective Tissue Growth Factor; Fibrosis; Heart; Hypertension; Male; MAP Kinase Signaling System; Mice; Myocardium; NADPH Oxidases; NF-kappa B; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Receptor, Angiotensin, Type 1; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Ventricular Remodeling

We investigated the association between left ventricular (LV) torsional deformation and vascular dysfunction, fibrosis, neurohumoral activation, and exercise capacity in patients with normal ejection fraction. In 320 newly-diagnosed untreated hypertensive patients and 160 controls, we measured: pulse wave velocity (PWV); coronary flow reserve (CFR) by Doppler echocardiography; global longitudinal strain and strain rate, peak twisting, the percentage changes between peak twisting, and untwisting at mitral valve opening (%dpTw - UtwMVO ), at peak (%dpTw - UtwPEF ), and the end of early LV diastolic filling (%dpTw - UtwEDF ) by speckle tracking imaging; transforming growth factor (TGFb-1), metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloptoteinase-1(TIMP-1), markers of collagen synthesis, and N-terminal pro-brain natriuretic peptide (NT-proBNP). Oxygen consumption (VO2 ), measured by means of cardiopulmonary exercise test, was assessed in a subset of 80 patients. The PWV, CFR, longitudinal strain and strain rate, %dpTw-UtwMVO , %dpTw-UtwPEF , and %dpTw-UtwEDF were impaired in hypertensive patients compared with controls. In multivariable analysis, CFR, PWV, LV mass, and systolic blood pressure were independent determinants of longitudinal strain, strain rate, and untwisting markers (P < 0.05). Increased TGFb-1 was related with increased collagen synthesis markers, TIMP-1 and MMP-9 and these biomarkers were associated with impaired longitudinal systolic strain rate, untwisting markers, CFR and PWV (P < 0.05). Delayed untwisting as assessed by reduced %dpTw - UtwEDF was related with increased NT-proBNP and reduced VO2 (P < 0.05).. Impaired LV untwisting is associated with increased arterial stiffness and coronary microcirculatory dysfunction, and is linked to reduced exercise capacity and neurohumoral activation in hypertensive heart disease. A fibrotic process may be the common link between vascular dysfunction and abnormal myocardial deformation.

Topics: Biomarkers; Blood Pressure; Echocardiography; Female; Heart Diseases; Heart Ventricles; Humans; Hypertension; Male; Matrix Metalloproteinase 9; Middle Aged; Mitral Valve; Natriuretic Peptide, Brain; Peptide Fragments; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

Endothelial dysfunction has been shown to be predictive of subsequent cardiovascular events and death. Through a mechanism that is incompletely understood, increased dietary salt intake promotes endothelial dysfunction in healthy, salt-resistant humans. The present study tested the hypothesis that dietary salt-induced transforming growth factor (TGF)-β promoted endothelial dysfunction and salt-dependent changes in blood pressure (BP). Sprague-Dawley rats that received diets containing 0.3% NaCl [low salt (LS)] or 8.0% NaCl [high salt (HS)] were treated with vehicle or SB-525334, a specific inhibitor of TGF-β receptor I/activin receptor-like kinase 5, beginning on day 5. BP was monitored using radiotelemetry in four groups of rats (LS, LS + SB-525334, HS, and HS + SB-525334) for up to 14 days. By day 14 of the study, mean daytime systolic BP and mean pulse pressure of the HS group treated with vehicle was greater than those in the other three groups; mean daytime systolic BP and pulse pressure of the HS + SB-525334 group did not differ from the LS and LS + SB-525334-treated groups. Whereas mean systolic BP, mean diastolic BP, and mean arterial pressure did not differ among the groups on the seventh day of the study, endothelium-dependent vasorelaxation was impaired specifically in the HS group; treatment with the activin receptor-like kinase 5 inhibitor prevented the dietary HS intake-induced increases in phospho-Smad2 (Ser(465/467)) and NADPH oxidase-4 in endothelial lysates and normalized endothelial function. These findings suggest that HS-induced endothelial dysfunction and the development of salt-dependent increases in BP were related to endothelial TGF-β signaling.

Topics: Animal Feed; Animals; Blood Pressure; Eating; Endothelium; Heart Rate; Hypertension; Male; Protein Serine-Threonine Kinases; Rats, Sprague-Dawley; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Sodium Chloride; Transforming Growth Factor beta; Vasodilation

More and more researches show that hypertensive vascular remodeling is closely related to the imbalance of immune system in recent years. IFN-γ is natural protein with the function of immune regulation and has resistance effect on vascular remodeling. However, the mechanism of IFN-γ is to be defined. This paper is to explore the mechanism of IFN-γ in regulating OPN/Th17 pathway. In this research, animal models of vascular collagen remodeling were established by inducing hypertensive mice with ANG II. There was no statistical significance when the systolic blood pressures and the percentages of wall thickness/lumen diameter in both groups of WT + AngII + IFN-γ and WT + PBS were compared (P=0.219>0.05, P=0.118>0.05). The concentration of serum precollagen-type I and III and their ratio in WT + AngII + IFN-γ group were decreased after the IFN-γ being given (P<0.01). Expression of OPN within tissue in WT + Ang II group was relatively high, but lowered after treated by IFN-γ. Th17 cell ratio was decreased in WT + AngII + IFN-γ group (P<0.01). Expressions of RORα and RORγt mRNA within Th17 cell were decreased (P<0.01). The content of IL-23 in WT + AngII + IFN-γ group was increased, while IL-10 and TGF-β decreased. It has proved that IFN-γ can regulate the hypertensive vascular collagen remodeling induced by ANG II, lower the systolic pressure and reduce the pathological damage of vascular collagen remodeling and the collagen synthesis. The mechanism may that the differentiation of Th17 is inhibited by suppressing the OPN expression and regulating the secretion of inflammatory cytokines.

Topics: Angiotensin II; Animals; Blood Pressure; Cell Differentiation; Cells, Cultured; Collagen Type I; Collagen Type III; Disease Models, Animal; Hypertension; Inflammation Mediators; Interferon-gamma; Interleukin-10; Interleukin-23; Mice, Inbred C57BL; Nuclear Receptor Subfamily 1, Group F, Member 1; Nuclear Receptor Subfamily 1, Group F, Member 3; Osteopontin; Procollagen; Spleen; Th17 Cells; Transforming Growth Factor beta; Vascular Remodeling

AngII (angiotensin II) is a potent neurohormone responsible for cardiac hypertrophy, in which TGF (transforming growth factor)-β serves as a principal downstream mediator. We recently found that ablation of fibulin-2 in mice attenuated TGF-β signalling, protected mice against progressive ventricular dysfunction, and significantly reduced the mortality after experimental MI (myocardial infarction). In the present study, we investigated the role of fibulin-2 in AngII-induced TGF-β signalling and subsequent cardiac hypertrophy. We performed chronic subcutaneous infusion of AngII in fibulin-2 null (Fbln2-/-), heterozygous (Fbln2+/-) and WT (wild-type) mice by a mini-osmotic pump. After 4 weeks of subpressor dosage of AngII infusion (0.2 μg/kg of body weight per min), WT mice developed significant hypertrophy, whereas the Fbln2-/- showed no response. In WT, AngII treatment significantly up-regulated mRNAs for fibulin-2, ANP (atrial natriuretic peptide), TGF-β1, Col I (collagen type I), Col III (collagen type III), MMP (matrix metalloproteinase)-2 and MMP-9, and increased the phosphorylation of TGF-β-downstream signalling markers, Smad2, TAK1 (TGF-β-activated kinase 1) and p38 MAPK (mitogen-activated protein kinase), which were all unchanged in AngII-treated Fbln2-/- mice. The Fbln2+/- mice consistently displayed AngII-induced effects intermediate between WT and Fbln2-/-. Pressor dosage of AngII (2 mg/kg of body weight per min) induced significant fibrosis in WT but not in Fbln2-/- mice with comparable hypertension and hypertrophy in both groups. Isolated CFs (cardiac fibroblasts) were treated with AngII, in which direct AngII effects and TGF-β-mediated autocrine effects was observed in WT. The latter effects were totally abolished in Fbln2-/- cells, suggesting that fibulin-2 is essential for AngII-induced TGF-β activation. In conclusion our data indicate that fibulin-2 is essential for AngII-induced TGF-β-mediated cardiac hypertrophy via enhanced TGF-β activation and suggest that fibulin-2 is a potential therapeutic target to inhibit AngII-induced cardiac remodelling.

Topics: Angiotensin II; Animals; Calcium-Binding Proteins; Cardiomegaly; Extracellular Matrix Proteins; Fibrosis; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardium; Signal Transduction; Transforming Growth Factor beta; Vasoconstrictor Agents

Despite the amount of information and research on the effects of virgin olive oil and its components in cardiovascular disease, little attention has been paid to the effects of pomace olive oil, an olive oil subproduct traditionally used in Spain. The aim of the present study was to evaluate the potential effects of a pomace olive oil concentrated in triterpenic acids (POCTA) on blood pressure, cardiac hemodynamics, and functional and molecular vascular alterations associated with hypertension in spontaneously hypertensive rats (SHR).. The study showed that POCTA attenuated the increase of blood pressure in SHR. This effect was associated with an improvement in endothelium-dependent relaxation, enhancement of vascular expression of endothelial nitric oxide synthase, and reduction of tumor necrosis factor alpha, transforming growth factor beta, and collagen I. Furthermore, POCTA improved cardiac hemodynamics (left ventricular systolic pressure and left ventricular end-diastolic pressure) and decreased relative kidney and lung weights.. POCTA exerts antihypertensive effects together with vascular and hypertension target organ protection in SHR. Since interest in pomace olive oil has been low, the results of this study contribute to increasing awareness of its biological and nutritional values.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Heart; Hemodynamics; Hypertension; Male; Nitric Oxide Synthase Type III; Olive Oil; Plant Oils; Rats; Rats, Inbred SHR; Spain; Transforming Growth Factor beta; Triterpenes; Tumor Necrosis Factor-alpha

Increasing age involves a number of detrimental changes in the cardiovascular system and particularly on the large arteries. It deteriorates vascular integrity and leads to increased vascular stiffness entailing hypertension with increased cardiovascular morbidity and mortality. The consequences of continuous oxidative stress and damages to biomolecules include altered gene expression, genomic instability, mutations, loss of cell division and cellular responses to increased stress. Many studies have been performed in aged C57BL/6 mice; however, analyses of the age-related changes that occur at a gene expression level and transcriptional profile in vascular tissue have not been elucidated in depth. To determine the changes of the vascular transcriptome, we conducted gene expression microarray experiments on aortas of adult and old mice, in which age-related vascular dysfunction was confirmed by increased stiffness and associated systolic hypertension. Our results highlight differentially expressed genes overrepresented in Gene Ontology categories. Molecular interaction and reaction pathways involved in vascular functions and disease, within the transforming growth factor-beta (TGF-β) pathway, the renin-angiotensin system and the detoxification systems are displayed. Our results provide insight to an altered gene expression profile related to age, thus offering useful clues to counteract or prevent vascular aging and its detrimental consequences.

Topics: Aging; Animals; Blood Pressure; Cardiovascular System; Gene Expression Profiling; Gene Expression Regulation; Hypertension; Male; Mice; Mice, Inbred C57BL; Microarray Analysis; Oligonucleotide Array Sequence Analysis; Oxidative Stress; Renin-Angiotensin System; Systole; Transforming Growth Factor beta

Loss of miR-29 is associated with cardiac fibrosis. This study examined the role and therapeutic potential of miR-29 in mouse model of hypertension induced by angiotensin II (AngII). By using microRNA microarray, in situ hybridization, and real-time polymerase chain reaction, we found that AngII-induced cardiac fibrosis in the hypertensive heart and in cultured cardiac fibroblasts were associated with downregulation of miR-29a-c via a Smad3-dependent mechanism. In vitro knockdown of miR-29b enhanced but overexpression of miR-29b inhibited AngII-induced fibrosis, revealing a protective role of miR-29b in cardiac fibrosis in response to AngII. This was further demonstrated in vivo by the ability of overexpressing miR-29b in the mouse heart to prevent AngII-mediated cardiac fibrosis and cardiac dysfunction. Importantly, we also found that restored miR-29b in the established hypertensive heart was capable of blocking progressive cardiac fibrosis and improving cardiac dysfunction, demonstrating a therapeutic potential of miR-29b for chronic heart disease. Further studies revealed that targeting the transforming growth factor (TGF)-β1 coding sequence region, thereby inhibiting TGF-β/Smad3 signaling, could be a new mechanism by which miR-29b inhibited AngII-induced cardiac fibrosis. In conclusion, miR-29b plays a protective role in AngII-mediated cardiac remodeling and may be a therapeutic agent for cardiac fibrosis by targeting the TGF-β/Smad3 pathway.

Topics: Angiotensin II; Animals; Disease Models, Animal; Endomyocardial Fibrosis; Gene Expression Regulation; Gene Knockdown Techniques; Humans; Hypertension; Mice; MicroRNAs; Molecular Targeted Therapy; Signal Transduction; Smad3 Protein; Transforming Growth Factor beta

Inflammation is implicated in the initiation of hypertension and end-organ injury. Interleukin-17A (IL-17A) is a key pathogenic factor in a variety of inflammatory diseases and hypertension. However, the mechanisms underlying IL-17A production, and its role in mediating inflammation and early cardiovascular injury in hypertensive heart, remain unknown. Angiotensin II (Ang II) infusion increased cardiac IL-17A mRNA expression and IL-17A+CD3+ cell infiltration in a time-dependent manner. IL-17A in the hypertensive heart was derived mostly from infiltrating γδT cells rather than from CD4 T cells. Genetic knockdown of γδT cells or specific anti-γδT antibody abolished IL-17A production in Ang II–infused heart. Moreover, monocyte-secreted IL-1β, not cardiac fibroblast–secreted IL-6 or transforming growth factor-β, was required for IL-17A production from γδT cell. IL-17A accelerated differentiation of myofibroblast through promoting IL-6 production from cardiac fibroblast. Finally, inflammatory cell infiltration, proinflammatory or profibrotic cytokine expression, and fibrotic lesion induced by Ang II were attenuated in IL-17A–deficient mice. Moreover, the deletion of γδT cell was protected from Ang II–induced cardiac injury. Thus, a triangular positive feedback loop exists among monocytic-secreted IL-1β, γδT-cell–derived IL-17A, and cardiac fibroblast–produced IL-6, which triggers the cardiac injury in hypertension.

Topics: Angiotensin II; Animals; Fibrosis; Hypertension; Interleukin-17; Interleukin-1beta; Interleukin-6; Mice; Myocardium; T-Lymphocytes; Transforming Growth Factor beta

Tulbaghia violacea has been used traditionally for the treatment of several ailments, including hypertension. The herb has been shown to have antihypertensive properties which have been attributed to its angiotensin-converting enzymeinhibitory (ACEI) activity. It could, therefore, prove beneficial in ameliorating renal pathology associated with hypertension. To evaluate the effects of long-term administration of Tulbaghia violacea on renal function and morphology in the Dahl salt-sensitive (DSS) rat model.. Male DSS rats were treated intra-peritoneally (i.p.) as follows: methanolic extract of Tulbaghia violacea: (TVL) (50 mg/kg/b.w.), captopril: (CAP) (25 mg/kg/b.w.), or distilled water, control: (CON) (3 ml/kg/b.w.). Blood pressure (BP) was measured bi-weekly, whilst 24-h urine volumes and electrolyte concentrations were assessed weekly. Animals were sacrificed on day 49 by halothane overdose. Blood was removed for determination of plasma and serum electrolytes. Left kidney tissues were harvested for the determination of nuclear factor-kappaβ (NF-kβ) and transforming growth factor-β (TGF-β) gene expressions.. TVL significantly reduced mean arterial pressure (MAP) and diastolic blood pressure (DBP). TVL showed reduced blood urea nitrogen, serum creatinine, total protein in urine as well as increased serum total protein. TVL decreased thiobarbituric acid reactive substances (TBARS) and increased glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity and nitric oxide significantly. NF-kβ and TGF-β) gene expressions were significantly reduced in TVL and CAP treated rats. Moreover, renal morphology improved significantly in TVL and CAP treated animals.. TVL and CAP demonstrated marked improvement in renal function and morphology.

Topics: Allium; Animals; Antihypertensive Agents; Arterial Pressure; Biomarkers; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Gene Expression Regulation; Hypertension; Injections, Intraperitoneal; Kidney; Male; Methanol; NF-kappa B; Oxidative Stress; Phytotherapy; Plant Extracts; Plants, Medicinal; Proteinuria; Rats, Inbred Dahl; Rhizome; Solvents; Time Factors; Transforming Growth Factor beta; Urodynamics

The plant Cecropia pachystachya Trécul has been used in Brazilian folk medicine to treat hypertension, bladder and kidney inflammation and renal diseases. The aim of this study was to evaluate the potential of the aqueous fraction from the ethanolic extract of Cecropia pachystachya (FCP) in the management of hypertension, inflammation and progressive renal disease in rats submitted to 5/6 nephrectomy.. Thirty male Wistar rats submitted to 5/6 nephrectomy (5/6 NE) were untreated (NE) or treated (NE+FCP) with the FCP (0.5g/kg/day). The treatment started 15 days after surgery, and the rats were followed for a period of 60 days. Systolic blood pressure (SBP) and albuminuria were evaluated from 15-60 days after the surgical procedure. Function and estructural renal changes, TGF-β (transforming growth factor β), MCP-1 (monocyte chemoattractant protein-1) and nitric oxide (NO) urinary excretion were analyzed. Expression and activity of the renal enzymes arginase (ARG), angiotensin converting enzyme (ACE), and MAP kinase p-JNK expression also were analyzed.. The nephrectomized rats developed progressive albuminuria and increased SBP that was less intense in the treated group. There was a reduction in the glomerular filtration rate (GFR) in the nephrectomized rats, which was attenuated by treatment with FCP extract. The treatment with FCP also attenuated the histological changes, reduced the expression and activity of renal arginase, the number of macrophages (ED-1 positive cells) and the p-JNK expression in the renal cortex of the rats submitted to 5/6 NE. The urinary excretion of TGF-β was less intense in the treated group and was associated with the reduction of the expression and activity of the renal arginase.. These results suggest that the reduction of renal arginase activity, p-JNK and TGF-β expression can explain the mechanism by which the treatment with C. pachystachya reduced the inflammation and improved renal function. This study presents the potential use of Cecropia pachystachya in the treatment of chronic renal diseases.

Topics: Albuminuria; Animals; Arginase; Brazil; Cecropia Plant; Disease Progression; Glomerular Filtration Rate; Hypertension; Inflammation; JNK Mitogen-Activated Protein Kinases; Kidney; Kidney Diseases; Male; Medicine, Traditional; Nephrectomy; Plant Extracts; Rats; Rats, Wistar; Transforming Growth Factor beta

Hypertensive heart disease is a constellation of abnormalities that includes cardiac fibrosis in response to elevated blood pressure, systolic and diastolic dysfunction. The present study was undertaken to examine the effect of sinapic acid on high blood pressure and cardiovascular remodeling.. An experimental hypertensive animal model was induced by L-NAME intake on rats. Sinapic acid (SA) was orally administered at a dose of 10, 20 and 40 mg/kg body weight (b.w.). Blood pressure was measured by tail cuff plethysmography system. Cardiac and vascular function was evaluated by Langendorff isolated heart system and organ bath studies, respectively. Fibrotic remodeling of heart and aorta was assessed by histopathologic analyses. Oxidative stress was measured by biochemical assays. mRNA and protein expressions were assessed by RT-qPCR and western blot, respectively. In order to confirm the protective role of SA on endothelial cells through its antioxidant property, we have utilized the in vitro model of H2O2-induced oxidative stress in EA.hy926 endothelial cells.. Rats with hypertension showed elevated blood pressure, declined myocardial performance associated with myocardial hypertrophy and fibrosis, diminished vascular response, nitric oxide (NO) metabolites level, elevated markers of oxidative stress (TBARS, LOOH), ACE activity, depleted antioxidant system (SOD, CAT, GPx, reduced GSH), aberrant expression of TGF-β, β-MHC, eNOS mRNAs and eNOS protein. Remarkably, SA attenuated high blood pressure, myocardial, vascular dysfunction, cardiac fibrosis, oxidative stress and ACE activity. Level of NO metabolites, antioxidant system, and altered gene expression were also repaired by SA treatment. Results of in vitro study showed that, SA protects endothelial cells from oxidative stress and enhance the production of NO in a concentration dependent manner.. Taken together, these results suggest that SA may have beneficial role in the treatment of hypertensive heart disease by attenuating fibrosis and oxidative stress through its antioxidant potential.

Topics: Animals; Anti-Infective Agents; Antioxidants; Blood Pressure; Cardiovascular Diseases; Cells, Cultured; Coumaric Acids; Enzyme Inhibitors; Hypertension; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxidative Stress; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta; Ventricular Remodeling

Hepatic stellate cells (HSCs) are important in the development of liver fibrosis and in the pathogenesis of portal hypertension. Octreotide, an analogue of somatostatin, has been demonstrated to effectively treat fibrosis and portal hypertension; however, its relative mechanism in HSCs remains unknown. LX‑2, the immortalized HSC line, was used to study the mechanism whereby octreotide functions at different concentrations. Real‑time polymerase chain reaction (PCR) and western blot analysis were used to analyze the expression of fibrosis markers and transcription factors following treatment with octreotide. Soluble secreted endothelin‑1 (ET‑1), collagen I and vascular endothelial growth factor (VEGF) were assessed in the supernatants of cultured cells by enzyme-linked immunosorbent assay (ELISA). In the present study, it was shown that octreotide was able to inhibit the proliferative ability of the LX‑2 cells and decrease the expression of transforming growth factor β (TGF‑β), α‑smooth muscle actin (α‑SMA) and smad‑4a. The transcription factors, including c‑Jun and sp‑1, were downregulated in a dose‑dependent manner following treatment with octreotide. The levels of ET‑1 and collagen I in the supernatant decreased significantly in contrast with the normal levels, whereas the levels of VEGF in the LX‑2 cells and the supernatant increased at a high octreotide concentration (10‑5 nM). Octreotide may exert its effects on ET‑1 or other targeting genes in HSCs through the downregulation of c‑Jun and specificity protein 1 (sp‑1), and the increased levels of VEGF may be the reason for the side effects observed at high concentrations of octreotide.

Topics: Actins; Cell Line; Cell Line, Transformed; Cell Proliferation; Collagen Type I; Endothelin-1; Fibroblasts; Fibrosis; Hepatic Stellate Cells; Humans; Hypertension; Liver; Octreotide; Proto-Oncogene Proteins c-jun; Smad4 Protein; Sp1 Transcription Factor; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

The albumin overload model induces proteinuria and tubulointersitial damage, followed by hypertension when rats are exposed to a hypersodic diet. To understand the effect of kinin system stimulation on salt-sensitive hypertension and to explore its potential renoprotective effects, the model was induced in Sprague-Dawley rats that had previously received a high-potassium diet to enhance activity of the kinin pathway, followed with/without administration of icatibant to block the kinin B₂ receptor (B₂R). A disease control group received albumin but not potassium or icatibant, and all groups were exposed to a hypersodic diet to induce salt-sensitive hypertension. Potassium treatment increased the synthesis and excretion of tissue kallikrein (Klk1/rKLK1) accompanied by a significant reduction in blood pressure and renal fibrosis and with downregulation of renal transforming growth factor-β (TGF-β) mRNA and protein compared with rats that did not receive potassium. Participation of the B₂R was evidenced by the fact that all beneficial effects were lost in the presence of the B₂R antagonist. In vitro experiments using the HK-2 proximal tubule cell line showed that treatment of tubular cells with 10 nM bradykinin reduced the epithelial-mesenchymal transdifferentiation and albumin-induced production of TGF-β, and the effects produced by bradykinin were prevented by pretreatment with the B₂R antagonist. These experiments support not only the pathogenic role of the kinin pathway in salt sensitivity but also sustain its role as a renoprotective, antifibrotic paracrine system that modulates renal levels of TGF-β.

Topics: Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Cell Line; Female; Fibrosis; Humans; Hypertension; Kidney Diseases; Kidney Tubules; Kinins; Metabolic Networks and Pathways; Potassium, Dietary; Proteinuria; Rats; Rats, Sprague-Dawley; Serum Albumin, Bovine; Sodium Chloride, Dietary; Tissue Kallikreins; Transforming Growth Factor beta

Benazepril, an angiotensin-converting enzyme (ACE) inhibitor, has been used to treat hypertension, congestive heart failure, and chronic renal failure. However, its biological activity and mechanism of action in inflammation are not fully identified. The present study was designed to determine the in vivo anti-inflammatory effects of benazepril on LV hypertrophy in rats.. LV hypertrophy was produced in rats by abdominal aortic coarctation. They were then divided into the following groups: sham operation; LV hypertrophy; LV hypertrophy+benazepril (1mg/kg in a gavage, once a day for 4 weeks). Both morphological assays (hemodynamic and hemorheological measurement; LV hypertrophy assessment), and molecular assays (protein levels of Collagen type I/III, TNF-α and VCAM-1; TGF-β gene expression; NF-κB or Smad activation; intracellular ROS production) were performed.. The following effects were observed in rats treated with benazepril: (1) marked improvements in hemodynamic and hemorheological parameters; (2) significant reductions in LV hypertrophy, dilatation and fibrosis; (3) significantly attenuated protein levels of Collagen type I/III, TGF-β, TNF-α and VCAM-1, NF-κB or Smad activation, as well as intracellular ROS production.. These results suggest that the anti-inflammatory properties of benazepril may be ascribed to their down-regulation of both NF-κB and TGF-β signaling pathways by acting on the intracellular ROS production in rats with LV hypertrophy, thus supporting the use of benazepril as an anti-inflammatory agent.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Aorta; Aortic Coarctation; Benzazepines; Blood Pressure; Collagen Type I; Collagen Type III; Enzyme Activation; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Inflammation; Male; NF-kappa B; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Vascular Cell Adhesion Molecule-1

Despite repair, a significant proportion of patients with coarctation of the aorta (CoA) present with late hypertension. Increased gene expression of aortic wall collagen and vascular smooth muscle cell markers occurs in the presence of hypertension. Before repair, a patent ductus arteriosus (PDA) limits hypertension proximal to the coarctation. We hypothesize that preoperative collagen and vascular smooth muscle expression from the aortic arch in children is variable, depending on the presence or absence of a PDA.. We analyzed the expression patterns of collagen and vascular smooth muscle cell markers in 25 children with CoA using a quantitative polymerase chain reaction. Aortic arch tissue proximal to the CoA was normalized to descending aortic tissue distal to the coarctation. Collagen-I, transforming growth factor-β, elastin, and calponin were analyzed.. At repair, 19 patients were aged younger than 3 months (14 with a PDA, 5 with a ligamentum arteriosum), and the remaining 6 were older than 1 year. There was no difference in age or weight between infants with or without a PDA. Infants without a PDA had the greatest difference in collagen-I expression compared with infants with a PDA (7.0 ± 1.6-fold vs 0.8 ± 1.1-fold, p = 0.01). Expression of transforming growth factor-β (4.3 ± 1.4 vs 2.6 ± 2.3, p = 0.01) and calponin (3.7 ± 0.7 vs 0.6 ± 1.1, p = 0.05) was lower from infants with vs without a PDA.. Our findings provide evidence of preoperative changes in the aortic arch before repair, particularly in the absence of a PDA.

Topics: Aorta, Thoracic; Aortic Coarctation; Calcium-Binding Proteins; Calponins; Child; Child, Preschool; Collagen Type I; Echocardiography; Female; Follow-Up Studies; Gene Expression Regulation; Humans; Hypertension; Infant; Infant, Newborn; Male; Microfilament Proteins; Muscle, Smooth, Vascular; Prognosis; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA; Transforming Growth Factor beta; Vascular Surgical Procedures

Smad7 plays a negative regulatory role in many inflammatory diseases, but its effect on hypertensive disease remains unknown. The present study tested the hypothesis that overexpression of Smad7 may have therapeutic potential for angiotensin II (Ang II)-mediated hypertensive cardiac remodelling.. Hypertensive heart disease was induced in mice by subcutaneous infusion of Ang II for 28 days and treated with Smad7 by a non-invasive ultrasound-microbubble-mediated inducible Smad7 gene transfer. We found that cardiac Smad7 was largely reduced in the hypertensive heart and overexpression of cardiac Smad7 protected against the fall in the left ventricular (LV) ejection fraction (EF), an increase in LV mass, and cardiac inflammation and fibrosis such as up-regulation of pro-inflammatory cytokines (IL-1β, TNF-α) and fibrotic markers (collagen I, α-SMA), and infiltration of CD3(+) T cells and F4/80(+) macrophages. Further studies revealed that inactivation of the Sp1-TGF-β/Smad3-NF-κB (NF-κB, nuclear factor κB) pathways and prevention of cardiac miR-29 loss were mechanisms by which overexpression of Smad7 inhibited Ang II-mediated cardiac remodelling. Importantly, we also found that treatment with Smad7 when hypertensive cardiopathy established at day 14 halted the progression of cardiac injury by blunting the fall of EF and an increase in LV mass, and blocking TGF-β/Smad3-mediated cardiac fibrosis and NF-κB-driven inflammation.. Smad7 plays a protective role in Ang II-induced cardiac remodelling via mechanisms involving the Sp1-TGF-β/Smad-NF-κB-miR-29 regulatory network. Thus, Smad7 may be a novel therapeutic agent for hypertensive cardiovascular diseases.

Topics: Angiotensin II; Animals; Fibrosis; Hypertension; Male; Mice; MicroRNAs; Myocardium; NF-kappa B; Smad7 Protein; Sp1 Transcription Factor; Transforming Growth Factor beta; Ventricular Remodeling

Platelets are essential for primary hemostasis; however, platelet activation also plays an important proinflammatory role. Inflammation promotes the development of cardiac fibrosis and heart failure induced by hypertension. In this study, we aimed to determine whether inhibiting platelet activation using clopidogrel could inhibit hypertension-induced cardiac inflammation and fibrosis.. Using a mouse model of angiotensin II (Ang II) infusion (1,500 ng/[kg·min] for 7 days), we determined the role of platelet activation in Ang II infusion-induced cardiac inflammation and fibrosis using a P2Y12 receptor inhibitor, clopidogrel (50 mg/[kg·day]).. CD41 staining showed that platelets accumulated in Ang II-infused hearts. Clopidogrel treatment inhibited Ang II infusion-induced accumulation of α-SMA(+) myofibroblasts and cardiac fibrosis (4.17 ± 1.26 vs. 1.46 ± 0.81, p < 0.05). Infiltration of inflammatory cells, including Mac-2(+) macrophages and CD45(+)Ly6G(+) neutrophils (30.38 ± 4.12 vs. 18.7 ± 2.38, p < 0.05), into Ang II-infused hearts was also suppressed by platelet inhibition. Real-time PCR and immunohistochemical staining showed that platelet inhibition significantly decreased the expression of interleukin-1β and transforming growth factor-β. Acute injection of Ang II or PE stimulated platelet activation and platelet-leukocyte conjugation, which were abolished by clopidogrel treatment.. Thus, inhibition of platelet activation by clopidogrel prevents cardiac inflammation and fibrosis in response to Ang II. Taken together, our results indicate Ang II infusion-induced hypertension stimulated platelet activation and platelet-leukocyte conjugation, which initiated inflammatory responses that contributed to cardiac fibrosis.

Topics: Angiotensin II; Animals; Clopidogrel; Fibrosis; Hypertension; Interleukin-1beta; Male; Mice; Mice, Inbred C57BL; Myocarditis; Myocardium; Platelet Activation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Ticlopidine; Transforming Growth Factor beta

The aim of this study was to investigate both the effects of chronic treatment with atrial natriuretic peptide (ANP) on systolic blood pressure (SBP), cardiac nitric oxide (NO) system, oxidative stress, hypertrophy, fibrosis and apoptosis in spontaneously hypertensive rats (SHR), and sex-related differences in the response to the treatment.. 10 week-old male and female SHR were infused with ANP (100 ng/hr/rat) or saline (NaCl 0.9%) for 14 days (subcutaneous osmotic pumps). SBP was recorded and nitrites and nitrates excretion (NOx) were determined. After treatment, NO synthase (NOS) activity, eNOS expression, thiobarbituric acid-reactive substances (TBARS) and glutathione concentration were determined in left ventricle, as well as the activity of glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD). Morphological studies in left ventricle were performed in slices stained with hematoxylin-eosin or Sirius red to identify collagen as a fibrosis indicator; immunohistochemistry was employed for identification of transforming growth factor beta; and apoptosis was evaluated by Tunel assay.. Female SHR showed lower SBP, higher NO-system activity and less oxidative stress, fibrosis and hypertrophy in left ventricle, as well as higher cardiac NOS activity, eNOS protein content and NOx excretion than male SHR. Although ANP treatment lowered blood pressure and increased NOS activity and eNOS expression in both sexes, cardiac NOS response to ANP was more marked in females. In left ventricle, ANP reduced TBARS and increased glutathione concentration and activity of CAT and SOD enzymes in both sexes, as well as GPx activity in males. ANP decreased fibrosis and apoptosis in hearts from male and female SHR but females showed less end-organ damage in heart. Chronic ANP treatment would ameliorate hypertension and end-organ damage in heart by reducing oxidative stress, increasing NO-system activity, and diminishing fibrosis and hypertrophy.

Topics: Animals; Antihypertensive Agents; Apoptosis; Atrial Natriuretic Factor; Blood Pressure; Catalase; Disease Models, Animal; Female; Glutathione; Heart; Hypertension; Male; Myocardium; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Rats, Inbred SHR; Sex Factors; Superoxide Dismutase; Transforming Growth Factor beta

Increased oxidative stress upregulates matrix metalloproteinases (MMPs) and transforming grow factor (TGF-β), which are involved in hypertensive cardiac remodeling. We tested the hypothesis that tempol (an antioxidant) could prevent these alterations in two-kidney, one-clip (2K1C) hypertension.. Sham-operated or hypertensive rats were treated with tempol (18 mg.kg(-1)day(-1) or vehicle) for 8 weeks. Systolic blood pressure was monitored weekly. At the end of the treatment, a catheter was inserted into the left carotid artery and into the left ventricle (LV) to assess arterial blood pressure and contractile function. Morphometry of the LV was carried out in hematoxylin/eosin sections and fibrosis was assessed in picrosirius red-stained sections. Cardiac TGF-β level was evaluated by immunofluorescence. Cardiac MMP-2 levels and activity were determined by gelatin zymography, in situ zymography, and immunofluorescence. Cardiac superoxide production was evaluated by dihydroethidium probe.. Tempol treatment attenuated 2K1C-induced hypertension and reversed the contractile dysfunction in 2K1C rats. Cardiac hypertrophy was ameliorated by antioxidant treatment. Hypertensive rats showed increased cardiac MMP-2 levels, however tempol did not decrease MMP-2 levels. Increased TGF-β level, total gelatinolytic activity and oxidative stress were found in untreated 2K1C rats. Tempol treatment decreased oxidative stress, TGF-β levels, and gelatinolytic activity in 2K1C rats to control levels.. Tempol blunted the increases in TGF-β, the proteolytic imbalance, and the morphological and functional alterations found in 2K1C-induced cardiac hypertrophy. These findings are consistent with the idea that antioxidants may help to prevent hypertension-induced cardiac hypertrophy.

Topics: Animals; Antioxidants; Cardiomegaly; Cardiotonic Agents; Cyclic N-Oxides; Hypertension; Male; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Rats; Rats, Wistar; Spin Labels; Transforming Growth Factor beta; Up-Regulation

We present a theoretical and computational model for collagen turnover in soft biological tissues. Driven by alterations in the mechanical environment, collagen fiber bundles may undergo important chronic changes, characterized primarily by alterations in collagen synthesis and degradation rates. In particular, hypertension triggers an increase in tropocollagen synthesis and a decrease in collagen degradation, which lead to the well-documented overall increase in collagen content. These changes are the result of a cascade of events, initiated mainly by the endothelial and smooth muscle cells. Here, we represent these events collectively in terms of two internal variables, the concentration of growth factor TGF-β and tissue inhibitors of metalloproteinases TIMP. The upregulation of TGF-β increases the collagen density. The upregulation of TIMP also increases the collagen density through decreasing matrix metalloproteinase MMP. We establish a mathematical theory for mechanically-induced collagen turnover and introduce a computational algorithm for its robust and efficient solution. We demonstrate that our model can accurately predict the experimentally observed collagen increase in response to hypertension reported in literature. Ultimately, the model can serve as a valuable tool to predict the chronic adaptation of collagen content to restore the homeostatic equilibrium state in vessels with arbitrary micro-structure and geometry.

Topics: Algorithms; Biomechanical Phenomena; Collagen; Humans; Hypertension; Matrix Metalloproteinases; Models, Biological; Muscle, Smooth; Tissue Inhibitor of Metalloproteinases; Transforming Growth Factor beta; Up-Regulation

Smad7 is an inhibitory Smad and plays a protective role in obstructive and diabetic kidney disease. However, the role and mechanisms of Smad7 in hypertensive nephropathy remains unexplored. Thus, the aim of this study was to investigate the role and regulatory mechanisms of Smad7 in ANG II-induced hypertensive nephropathy. Smad7 gene knockout (KO) and wild-type (WT) mice received a subcutaneous infusion of ANG II or control saline for 4 weeks via osmotic mini-pumps. ANG II infusion produced equivalent hypertension in Smad7 KO and WT mice; however, Smad7 KO mice exhibited more severe renal functional injury as shown by increased proteinuria and reduced renal function (both p<0.05) when compared with Smad7 WT mice. Enhanced renal injury in Smad7 KO mice was associated with more progressive renal fibrosis with elevated TGF-β/Smad3 signalling. Smad7 KO mice also showed more profound renal inflammation including increased macrophage infiltration, enhanced IL-1β and TNF-α expression, and a marked activation of NF-κB signaling (all p<0.01). Further studies revealed that enhanced ANG II-mediated renal inflammation and fibrosis in Smad7 KO mice were also associated with up-regulation of Sp1 but downregulation of miR-29b expression. Taken together, the present study revealed that enhanced Sp1-TGF-β1/Smad3-NF-κB signaling and loss of miR-29 may be mechanisms by which deletion of Smad7 promotes ANG II-mediated renal fibrosis and inflammation. Thus, Smad7 may play a protective role in ANG II-induced hypertensive kidney disease.

Topics: Angiotensin II; Animals; Fibrosis; Gene Expression Regulation; Hypertension; Inflammation; Kidney; Kidney Diseases; Male; Mice; Mice, Knockout; MicroRNAs; NF-kappa B; Proteinuria; Signal Transduction; Smad3 Protein; Smad7 Protein; Sp1 Transcription Factor; Transforming Growth Factor beta

Although relaxin (RLX) has potent vasodilatory and anti-fibrotic properties, there is no information on its effects on salt-sensitive hypertension.. We investigated the effects of short-term treatment with RLX on blood pressure (BP) and nitric oxide synthase (NOS) protein in the kidneys of male Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) rats after 1 week consumption of an 8% NaCl diet. We also evaluated the inhibitory effects of each specific NOS inhibitor on BP during 1-week RLX treatment under high-salt diet. Next, we examined the long-term effects of RLX treatment for 6 weeks on renal histology and transforming growth factor-beta1 (TGF-β1) expression in male DS and DR rats placed on the 8-week high-salt diet.. The short-term RLX treatment significantly attenuated the high-salt diet-induced rise in BP in DS rats with increasing neuronal NOS and endothelial NOS protein in kidneys. Selective inhibition of each of the three NOS isoforms significantly blocked the anti-hypertensive effects of RLX in DS rats after 1-week high-salt diet. The long-term treatment of DS rats with RLX for 6 weeks significantly reduced systolic BP, lessened glomerular and tubulointerstitial changes and reduced TGF-β signaling compared to saline-treated controls.. The results suggested that RLX converted salt sensitivity to salt resistance, at least in part, by up-regulating NOS. RLX is a potentially useful therapeutic agent for salt-sensitive hypertension.

Topics: Animals; Blood Pressure; Blotting, Western; Fibrosis; Hypertension; Immunoenzyme Techniques; Kidney Diseases; Male; Nitric Oxide Synthase; Rats; Rats, Inbred Dahl; Relaxin; Smad Proteins; Sodium Chloride, Dietary; Transforming Growth Factor beta

This study was designed to investigate the effects and mechanism of action of the traditional Chinese drug formula, qiliqiangxin (QLQX), on cardiac function in spontaneously hypertensive rats (SHRs).. We evaluated the effects of oral high-dose (4 g/kg/day, n = 7) and low-dose (1 g/kg/day, n = 7) QLQX on cardiac function in SHRs aged between 8 compared to control, the 8-week-old Wistar-Kyoto (WKY) rats. Echocardiography was performed to evaluate cardiac function and hemodynamic parameters. Hematoxylin and eosin (HE) and Masson's trichrome staining were performed, and the expression of myocardial angiotensin (Ang)-converting enzyme, chymase, transforming growth factor (TGF)-β, and collagen-type I and III were evaluated with real-time reverse transcription-PCR. Myocardial chymase, Ang-converting enzyme (ACE), and Ang II activities were measured with radioimmunoassay (RIA) techniques. Cardiac mast cells were detected with toluidine blue staining.. In SHRs, the number of chymase enzyme-positive mast cells increased in the left ventricle (LV) compared with WKY rats. QLQX significantly decreased mast cell density and cardiac chymase levels, and it improved ejection fraction values and cardiac systolic function compared with vehicle. Moreover, QLQX decreased left atrial diameters and improved the E/A ratio. QLQX suppressed collagen-type I and III and TGF-β mRNA levels, and Ang II activity, in a dose-dependent manner. Whereas no difference in ACE activity was found between SHRs, chymase expression and activity were significantly decreased with QLQX.. These data suggest that QLQX improves both systolic and diastolic cardiac function in SHRs through downregulating the cardiac chymase signaling pathway and chymase-mediated Ang II production.

Topics: Animals; Blood Pressure; Chymases; Collagen Type I; Collagen Type III; Drugs, Chinese Herbal; Echocardiography; Heart; Hypertension; Male; Mast Cells; Medicine, Chinese Traditional; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Transforming Growth Factor beta

Although Smad3 is a key mediator for fibrosis, its functional role and mechanisms in hypertensive nephropathy remain largely unclear. This was examined in the present study in a mouse model of hypertension induced in Smad3 knockout (KO) and wild-type (WT) mice by subcutaneous angiotensin II infusion and in vitro in mesangial cells lacking Smad3. After angiotensin II infusion, both Smad3 KO and WT mice developed equally high levels of blood pressure. However, disruption of Smad3 prevented angiotensin II-induced kidney injury by lowering albuminuria and serum creatinine (P < 0.01), inhibiting renal fibrosis such as collagen type I and IV, fibronectin, and α-SMA expression (all P < 0.01), and blocking renal inflammation including macrophage and T cell infiltration and upregulation of IL-1β, TNF-α, and monocyte chemoattractant protein-1 in vivo and in vitro (all P < 0.001). Further studies revealed that blockade of angiotensin II-induced renal transforming growth factor (TGF)-β1 expression and inhibition of Smurf2-mediated degradation of renal Smad7 are mechanisms by which Smad3 KO mice were protected from angiotensin II-induced renal fibrosis and NF-κB-driven renal inflammation in vivo and in vitro. In conclusion, Smad3 is a key mediator of hypertensive nephropathy. Smad3 promotes Smurf2-dependent ubiquitin degradation of renal Smad7, thereby enhancing angiotensin II-induced TGF-β/Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation. Results from this study suggest that inhibition of Smad3 or overexpression of Smad7 may be a novel therapeutic strategy for hypertensive nephropathy.

Topics: Actins; Albuminuria; Angiotensin II; Animals; Chemokine CCL2; Collagen Type I; Collagen Type IV; Creatinine; Female; Fibronectins; Fibrosis; Hypertension; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; Smad3 Protein; Smad7 Protein; Transforming Growth Factor beta; Ubiquitin-Protein Ligases

Emerging evidence has shown that podocyte injury and reduced specific podocyte protein expressions contribute to proteinuria in preeclampsia. We collected urine specimens from women with preeclampsia to study whether podocyte-specific protein shedding is associated with renal barrier dysfunction. Urine specimens from women with normal pregnancies and from pregnant women complicated by chronic hypertension were used for comparison. We determined soluble podocyte slit protein nephrin levels in the urine specimens. Podocalyxin, βig-h3, and VEGF concentrations were also measured. We found that nephrin and podocalyxin were barely detectable in the urine specimens from normal pregnant women and from women with chronic hypertension. In preeclampsia, urinary nephrin and podocalyxin concentrations were significantly increased and highly correlated to each other, r(2) = 0.595. Nephrin and podocalyxin were also correlated with urine protein concentrations. βig-h3 was detected in the urine specimens from women with preeclampsia, and it is highly correlated with nephrin and podocalyxin concentrations in preeclampsia. βig-h3 was undetectable in normal pregnancy and pregnancy complicated by chronic hypertension. Elevated VEGF levels were also found in women with preeclampsia compared with those of normal pregnancy and pregnancy complicated by chronic hypertension. These results provide strong evidence that podocyte protein shedding occurs in preeclampsia, and their levels are associated with proteinuria. The finding of urinary βig-h3 excretion in preeclampsia suggests that increased transforming growth factor activity might also be involved in the kidney lesion in this pregnancy disorder.

Topics: Adult; Biomarkers; Case-Control Studies; Extracellular Matrix Proteins; Female; Humans; Hypertension; Kidney; Membrane Proteins; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Sialoglycoproteins; Signal Transduction; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

The mechanisms underlying cardiac fibrosis in hypertension are yet to be defined, although inflammatory cells, fibroblasts, and cytokines have been implicated. Here, we investigated the role of interleukin-4 (IL-4) in cardiac fibrosis, which is elevated in the hypertensive heart. IL-4 has been shown to be pro-fibrotic in the liver and the lung, but its role in cardiac fibrosis has not been investigated.. Cardiac fibrosis was induced in mice by constricting the aorta between the two carotid arteries. Fourteen days later marked left ventricular fibrosis developed together with expression of IL-4. Anti-IL-4 neutralizing antibodies attenuated this fibrosis without affecting blood pressure or expression of the transforming growth factor-beta system. The reduction in fibrosis was associated with reductions in interstitial fibroblasts and macrophages together with reductions in proliferating cells and expression of monocyte chemoattractant protein-1 (MCP-1). Since mast cells are a source of IL-4, we also assessed their role in fibrosis. Cromolyn, a mast cell inhibitor attenuated mast cell degranulation as well as IL-4 mRNA expression and cardiac fibrosis without affecting blood pressure. Treatment with Cromolyn also reduced interstitial fibroblasts and macrophages in regions of developing fibrosis as well MCP-1 expression.. This study demonstrates for the first time that IL-4, most likely produced by mast cells in the heart during pressure overload, is a significant contributor to cardiac fibrosis. Targeting this cytokine may be a useful therapeutic strategy to limit cardiac fibrosis.

Topics: Animals; Aortic Coarctation; Cell Proliferation; Fibrosis; Hypertension; Interleukin-4; Macrophages; Male; Mast Cells; Mice; Mice, Inbred C57BL; Myocardium; Reactive Oxygen Species; Transforming Growth Factor beta

This study examined the effects of anti-TGF-β antibody (1D11) therapy in Dahl S (S) rats fed a 4% NaCl diet. Baseline renal expression of TGF-β1 and the degree of injury were lower in female than male S rats maintained on a 0.4% NaCl diet. 4% NaCl diet increased mean arterial pressure (MAP), proteinuria, and renal injury to the same extent in both male and female S rats. Chronic treatment with 1D11 had renoprotective effects in both sexes. The ability of 1D11 to oppose the development of proteinuria when given alone or in combination with antihypertensive agents was further studied in 6-wk-old female S rats, since baseline renal injury was less than that seen in male rats. 1D11, diltiazem, and hydrochlorothiazide (HCT) attenuated the development of hypertension, proteinuria, and glomerular injury. 1D11 had no additional effect when given in combination with these antihypertensive agents. We also explored whether 1D11 could reverse renal injury in 9-wk-old male S rats with preexisting renal injury. MAP increased to 197 ± 4 mmHg and proteinuria rose to >300 mg/day after 3 wk on a 4% NaCl diet. Proteinuria was reduced by 30-40% in rats treated with 1D11, HCT, or captopril + 1D11, but the protective effect was lost in rats fed the 4% NaCl diet for 6 wk. Nevertheless, 1D11, HCT, and captopril + 1D11 still reduced renomedullary and cardiac fibrosis. These results indicate that anti-TGF-β antibody therapy reduces renal and cardiac fibrosis and affords additional renoprotection when given in combination with various antihypertensive agents in Dahl S rats.

Topics: Acute Kidney Injury; Animals; Antibodies, Anti-Idiotypic; Antihypertensive Agents; Blood Pressure; Captopril; Diltiazem; Disease Models, Animal; Female; Fibrosis; Hydrochlorothiazide; Hypertension; Male; Proteinuria; Rats; Rats, Inbred Dahl; Sex Characteristics; Sodium Chloride, Dietary; Transforming Growth Factor beta

Emilin-1 is a protein of elastic extracellular matrix involved in blood pressure (BP) control by negatively affecting transforming growth factor (TGF)-β processing. Emilin1 null mice are hypertensive. This study investigates how Emilin-1 deals with vascular mechanisms regulating BP.. This study uses a phenotype rescue approach in which Emilin-1 is expressed in either endothelial cells or vascular smooth muscle cells of transgenic animals with the Emilin1(-/-) background. We found that normalization of BP required Emilin-1 expression in smooth muscle cells, whereas expression of the protein in endothelial cells did not modify the hypertensive phenotype of Emilin1(-/-) mice. We also explored the effect of treatment with anti-TGF-β antibodies on the hypertensive phenotype of Emilin1(-/-) mice, finding that neutralization of TGF-β in Emilin1 null mice normalized BP quite rapidly (2 weeks). Finally, we evaluated the vasoconstriction response of resistance arteries to perfusion pressure and neurohumoral agents in different transgenic mouse lines. Interestingly, we found that the hypertensive phenotype was coupled with an increased arteriolar myogenic response to perfusion pressure, while the vasoconstriction induced by neurohumoral agents remained unaffected. We further elucidate that, as for the hypertensive phenotype, the increased myogenic response was attributable to increased TGF-β activity.. Our findings clarify that Emilin-1 produced by vascular smooth muscle cells acts as a main regulator of resting BP levels by controlling the myogenic response in resistance arteries through TGF-β.

Topics: Animals; Antibodies, Neutralizing; Arterioles; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Dose-Response Relationship, Drug; Echocardiography, Doppler; Endothelial Cells; Gene Expression Regulation; Genotype; Humans; Hypertension; Membrane Glycoproteins; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Muscle, Smooth, Vascular; Nitric Oxide Synthase Type III; Phenotype; Telemetry; Time Factors; Transforming Growth Factor beta; Vasoconstriction; Vasoconstrictor Agents

To examine nicotine (N) and cotinine (C) effects on trophoblast cells (TCs) and human umbilical vein endothelial cells (HUVEC) secretion of soluble fms-like tyrosine kinase (sFlt-1), soluble endoglin (sENG), placental growth factor (PlGF), transforming growth factor-beta (TGF-beta) and vascular endothelial growth factor (VEGF).. Human placentas and umbilical cords were collected from uncomplicated pregnancies at term from a total of 24 non-smoking women with a history of normal blood pressure. TCs and HUVEC were cultured for 24 h with C or N (from 10(-12) to 10(-7) M).. sFlt-1, sENG, PlGF, TGF-beta and VEGF release and messenger RNA (mRNA) expression were evaluated by ELISA and real-time polymerase chain reaction (PCR), respectively.. N and C reduced sFlt-1, sENG and PlGF release by TCs and TGF-beta release by HUVEC. Conversely, N and C increased PlGF secretion, while N alone increased sFlt-1 release by HUVEC. N and C were able to modulate VEGF mRNA expression in HUVEC.. Our results suggest that N and C affect the balance of some important vasoactive factors released by TCs and HUVEC. This might be one of the possible mechanism through which smoke reduces the risk of hypertensive disorders during pregnancy as well as contributes to the well known detrimental effects of smoking on fetal development.

Topics: Antigens, CD; Cotinine; Endoglin; Endothelium, Vascular; Female; Humans; Hypertension; Nicotine; Placenta Growth Factor; Pregnancy; Pregnancy Proteins; Receptors, Cell Surface; Smoking; Transforming Growth Factor beta; Trophoblasts; Umbilical Veins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Cilnidipine, an N/L-type calcium channel blocker, has been reported to inhibit sympathetic nerve activity and has a greater renoprotective effect than L-type calcium channel blockers. To investigate the hypothesis that cilnidipine might ameliorate advanced hypertensive nephropathy and inhibit the renal renin-angiotensin-aldosterone system, cilnidipine (1 mg per kg per day) or amlodipine (1 mg per kg per day) was administered to uninephrectomized deoxycorticosterone (DOCA)-salt hypertensive rats (DOCA-salt) for 4 weeks by gavage. Although the blood pressure in the DOCA-salt group was higher than that of control, neither cilnidipine nor amlodipine had any effect on the increase in blood pressure in the DOCA-salt group. The DOCA (40 mg per kg per week, subcutaneously (s.c.)) and salt (1% NaCl in drinking water) treatment significantly aggravated the levels of urinary protein excretion and creatinine clearance and increased glomerulosclerosis and collagen deposition in the tubulointerstitial area of the kidney. These effects were attenuated by cilnidipine treatment. Reverse transcription-polymerase chain reaction analysis revealed that the renal expression of mRNA for collagen I/IV and transforming growth factor-β was enhanced in the DOCA-salt group and that the overexpression of these molecules was suppressed by cilnidipine. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived superoxide production in the kidney and urinary norepinephrine excretion, which were enhanced in the DOCA-salt group, were suppressed by cilnidipine. Cilnidipine also decreased the activity and expression of angiotensin-converting enzyme (ACE) and the aldosterone concentration in the renal homogenate. Although neither cilnidipine nor amlodipine had any effect on the increased blood pressure in the DOCA-salt group, these renal changes were not induced by treatment with amlodipine. In conclusion, cilnidipine inhibited renal dysfunction, sympathetic nerve activity and renal renin-angiotensin-aldosterone system in the DOCA-salt group.

Topics: Amlodipine; Animals; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Collagen; Desoxycorticosterone; Dihydropyridines; Disease Models, Animal; Hypertension; Intracellular Signaling Peptides and Proteins; Kidney; Male; Membrane Proteins; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; Sodium Chloride; Transforming Growth Factor beta; Treatment Outcome

Transforming growth factor (TGF)-β is one of the main fibrogenic cytokines that drives the pathophysiology of progressive renal scarring. MicroRNAs (miRNAs) are endogenous non-coding RNAs that post-transcriptionally regulate gene expression. We examined the role of TGF-β-induced expression of miR-21, miRNAs in cell culture models and miRNA expression in relevant models of renal disease. In vitro, TGF-β changed expression of miR-21, miR-214, and miR-145 in rat mesangial cells (CRL-2753) and miR-214, miR-21, miR-30c, miR-200b, and miR-200c during induction of epithelial-mesenchymal transition in rat tubular epithelial cells (NRK52E). miR-214 expression was robustly modulated in both cell types, whereas in tubular epithelial cells miR-21 was increased and miR-200b and miR-200c were decreased by 58% and 48%, respectively, in response to TGF-β. TGF-β receptor-1 was found to be a target of miR-200b/c and was down-regulated after overexpression of miR-200c. To assess the differential expression of these miRNAs in vivo, we used the anti-Thy1.1 mesangial glomerulonephritis model and the unilateral ureteral obstruction model in which TGF-β plays a role and also a genetic model of hypertension, the stroke-prone spontaneously hypertensive rat with and without salt loading. The expressions of miR-214 and miR-21 were significantly increased in all in vivo models, showing a possible miRNA signature of renal damage despite differing causes.

Topics: Animals; Disease Models, Animal; Gene Expression Regulation; Glomerulonephritis; Hypertension; Kidney; Kidney Glomerulus; Kidney Tubules; Male; MicroRNAs; Rats; Rats, Inbred WKY; Time Factors; Transforming Growth Factor beta; Ureter

To determine clinical significance of urinary biomarkers of proteolysis/fibrinolysis and fibroangiogenesis in essential hypertension (EH).. Examination of the kidneys was made in 71 patients with EH degree 1-3. Renal function was assessed by 24-h albuminuria, calculated glomerular filtration rate (GFR) by Cockroft-Golt. Early signs of renal damage were microalbuminuria--MAU (diurnal albuminuria 30-300 mg/day), reduction of GFR (< 90 ml/min/1.73 m2). EH patients with hypercreatininemia and GFR under 60 ml/min/1.73m2 corresponding to stage III of chronic kidney disease were not included in the study. An additional nephropathy marker was an elevated index of resistance of interlobular renal arteries (RI > 0.65) as shown by dopplerometry. ELISA examined urinary biomarkers of intercellular and cell-matrix interactions in the kidney in EHpatients and healthy controls (n = 12).. MAU was detected in 54 (76%) of 71 EH patients, elevated RI > 0.65--in 37 (52%) patients. Urinary biomarkers of proteolysis/fibrinolysis and fibroangiogenesis were higher in EH patients then in the controls. Urinary excretion of PAI-1, TGF-beta1, VEGF and collagen of type IV in EH patients with MAU was significantly higher than in patients with normoalbuminuria. A strong direct correlation between MAU and the rest above urinary biomarkers was found as well as between urinary excretion of collagen IV and RI. An inverse negative relationship was seen between RI and GFR.. Renal impairment in EHpatients is a progressive disorder. Each stage of this process has its own clinicodiagnostic markers. Urinary biomarkers ofproteolysis/fibrinolysis and fibroangiogenesis in the kidney are informative for monitoring of early HNP.

Topics: Adolescent; Adult; Aged; Albuminuria; Biomarkers; Collagen Type IV; Female; Fibrinolysis; Glomerular Filtration Rate; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Monitoring, Physiologic; Neovascularization, Pathologic; Plasminogen Activator Inhibitor 1; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Young Adult

To investigate the effects of the transient receptor potential vanilloid type 1 (TRPV1) channel on renal extracellular matrix (ECM) protein expression including collagen deposition and the transforming growth factor β (TGF-β)/Smad signaling pathway during salt-dependent hypertension, wild-type (WT) and TRPV1-null (TRPV1⁻/⁻) mutant mice were uninephrectomized and given deoxycorticosterone acetate (DOCA)-salt for 4 wks. TRPV1 gene ablation exaggerated DOCA-salt-induced impairment of renal function as evidenced by increased albumin excretion (μg/24 h) compared with WT mice (83.7 ± 7.1 versus 28.3 ± 4.8, P < 0.05), but had no apparent effect on mean arterial pressure (mmHg) as determined by radiotelemetry (141 ± 4 versus 138 ± 3, P > 0.05). Morphological analysis showed that DOCA-salt-induced glomerulosclerosis, tubular injury and macrophage infiltration (cells/mm²) were increased in TRPV1⁻/⁻ compared with WT mice (0.74 ± 0.08 versus 0.34 ± 0.04; 3.14 ± 0.26 versus 2.00 ± 0.31; 68 ± 5 versus 40 ± 4, P < 0.05). Immunostaining studies showed that DOCA-salt treatment decreased nephrin but increased collagen type I and IV as well as phosphorylated Smad2/3 staining in kidneys of TRPV1⁻/⁻ compared with WT mice. Hydroxyproline assay and Western blot showed that DOCA-salt treatment increased collagen content (μg/mg dry tissue) and fibronectin protein expression (%β-actin arbitrary units) in the kidney of TRPV1⁻/⁻ compared with WT mice (26.7 ± 2.7 versus 17.4 ± 1.8; 0.93 ± 0.07 versus 0.65 ± 0.08, P < 0.05). Acceleration of renal ECM protein deposition in DOCA-salt-treated TRPV1⁻/⁻ mice was accompanied by increased TGF-β1, as well as phosphorylation of Smad2/3 protein expression (%β-actin arbitrary units) compared with DOCA-salt-treated WT mice (0.61 ± 0.07 versus 0.32 ± 0.05; 0.57 ± 0.07 versus 0.25 ± 0.05; 0.71 ± 0.08 versus 0.40 ± 0.06, P < 0.05). These results show that exaggerated renal functional and structural injuries are accompanied by increased production of ECM protein and activation of the TGF-β/Smad2/3 signaling pathway. These data suggest that activation of TRPV1 attenuates the progression of renal fibrosis possibly via suppression of the TGF-β and its downstream regulatory signaling pathway.

Topics: Animals; Blood Pressure; Desoxycorticosterone; Fibronectins; Fibrosis; Heart Rate; Hypertension; Kidney; Kidney Cortex; Kidney Diseases; Kidney Glomerulus; Mice; Phosphorylation; Protective Agents; Signal Transduction; Smad Proteins; Smad2 Protein; Smad3 Protein; Time Factors; Transforming Growth Factor beta; TRPV Cation Channels

Chronic heart failure (CHF) is associated with increased inflammation, and exercise training has in some studies been shown to have anti-inflammatory effect, although controversies exist. We investigated the effects of exercise training in CHF patients on markers of inflammation, and further explored any association between inflammation and the severity and etiology of the disease.. Eighty patients in stable CHF were randomized to 4 months of group-based high intensity exercise training or to a control group. Physical capacity was measured by 6-minute walk test and cycle ergometer test. Blood samples were drawn at baseline, after 4 months and after 12 months follow-up for analyses of a range of biomarkers.. Physical capacity was significantly inversely related to CRP, IL-6, VCAM-1 and TGF-β, and NT pro-BNP levels were significantly correlated to CRP, TNF-α, IL-6, VCAM-1, ICAM-1 and TGF-β (p < 0.05 for all). Patients with hypertension as etiology of CHF showed higher levels of CRP (p < 0.01), IL-6 (p = 0.05) and TNF-α (p = 0.02) as compared to other etiologies. No significant differences in changes between the exercise group and the control group were obtained in any of the measured variables, except in patients with idiopathic dilated cardiomyopathy (IDCM), where significant reductions in CRP, ICAM-1, TGF-β and TNF-α levels were observed (p < 0.05 for all).. Measures of CHF severity were significantly correlated with several markers of inflammation. We could not demonstrate over-all anti-inflammatory effect of exercise in this population of CHF patients. However, the etiology of CHF affected the inflammatory profile and the effect of exercise training.

Topics: Aged; Biomarkers; C-Reactive Protein; Chronic Disease; Exercise; Exercise Test; Exercise Therapy; Female; Follow-Up Studies; Heart Failure; Humans; Hypertension; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Middle Aged; Norway; Severity of Illness Index; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1

Oxidative stress has been shown to play an important role in the development of hypertensive renal injury. Peroxisome proliferator-activated receptors alpha (PPARalpha) has antioxidant effect. In this study, we demonstrated that fenofibrate significantly reduced proteinuria, inflammatory cell recruitment and extracellular matrix (ECM) proteins deposition in the kidney of SHRs without apparent effect on blood pressure. To investigate the mechanisms involved, we found that fenofibrate treatment markedly reduced oxidative stress accompanied by reduced activity of renal NAD(P)H oxidase, increased activity of Cu/Zn SOD, and decreased phosphorylation of p38MAPK and JNK in the kidney of SHRs. Taken together, fenofibrate treatment can protect against hypertensive renal injury without affecting blood pressure by inhibiting inflammation and fibrosis via suppression of oxidative stress and MAPK activity.

Topics: Animals; Antioxidants; Collagen; Fenofibrate; Hypertension; Kidney Diseases; Male; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase Kinases; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; PPAR alpha; Rats; Rats, Inbred SHR; Superoxide Dismutase; Transforming Growth Factor beta

Based on a case-control study, we investigated the relationship between +869T/C and +915G/C gene polymorphisms in transforming growth factor-beta1 (TGF-beta1), protein levels and essential hypertension (EH) in the Kazakh and Han Chinese populations selected from the Boertonggu countryside of Shawan region in the Xinjiang Uygur Autonomous Region of China (n=1600). The polymorphisms of TGF-beta1 and the blood levels were detected using polymerase chain reaction-restriction fragment length polymorphism assays and sandwich ELISA, respectively.. An association was found between +869C-allele with higher risk of EH in these two populations. We also found that the CG haplotype of the two polymorphisms was associated with EH in the Kazakh EH patients. The levels of TGF-beta(1) in the blood were positively correlated with diastolic blood pressure both in the Kazakh and Han EH patients. Levels of the TGF-beta1 protein in the Kazakh EH patients were significantly higher than those in the Han EH patients.. These results suggest that the TGF-beta1 +869 C allele is potentially a genetic factor of EH in these two ethnicities, the CG haplotype can be a genetic marker of EH in the Kazakh Chinese and the high concentration of TGF-beta1 is possibly associated with EH, especially in the Kazakh population.

Topics: Adolescent; Adult; Aged; Blood Pressure; Case-Control Studies; China; Exons; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Hypertension; Linkage Disequilibrium; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Polymorphism, Single Nucleotide; Transforming Growth Factor beta; Young Adult

Angiotensin receptor blockers (ARBs) or T- and L-type calcium channel blockers (CCBs) are useful for glomerular protection; however, the protective effects of combination therapy remain unclear. In this study, Dahl salt-sensitive rats were fed a high-salt diet and were treated daily with placebo, irbesartan (60 mg kg(-1)), efonidipine (30 mg kg(-1)), irbesartan (60 mg kg(-1))+efonidipine (30 mg kg(-1)), amlodipine (3 mg kg(-1)), or irbesartan (60 mg kg(-1))+amlodipine (3 mg kg(-1)) for 4 weeks. Significant reductions in systolic blood pressure were seen in the irbesartan-, efonidipine- and amlodipine-treated groups compared with the placebo-treated group; a further significant reduction was seen in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group. Compared with the placebo-treated group, proteinuria was significantly lower in the irbesartan- and efonidipine-treated groups, but not in the amlodipine-treated group. Furthermore, a significant attenuation of proteinuria in the irbesartan+efonidipine-treated group compared with the irbesartan-treated group was observed; this effect was not observed in the irbesartan+amlodipine-treated group. The glomerulosclerosis index was significantly attenuated by all active treatments except amlodipine. The glomerulosclerosis index in the irbesartan+efonidipine-treated group, but not in the irbesartan+amlodipine-treated group, was significantly lower than that in the irbesartan-treated group. Significant attenuations of gene expressions of p22(phox), transforming growth factor-beta, monocyte chemoattractant protein-1 and collegen I were observed in the irbesartan- and efonidipine-treated groups, but not in the amlodipine-treated group. Values for these parameters were reduced to control levels in the irbesartan+efonidipine-treated group. Combination therapy with ARB and T- and L-type CCB might produce a powerful renal protective effect.

Topics: Amlodipine; Angiotensin II Type 1 Receptor Blockers; Animals; Biphenyl Compounds; Blood Pressure; Calcium Channel Blockers; Chemokine CCL2; Collagen Type I; Dihydropyridines; Drug Therapy, Combination; Gene Expression; Glomerulosclerosis, Focal Segmental; Hypertension; Irbesartan; Kidney Glomerulus; Male; NADPH Oxidases; Nitrophenols; Organophosphorus Compounds; Proteinuria; Rats; Rats, Inbred Dahl; Tetrazoles; Transforming Growth Factor beta

Adiposity contributes to the insulin resistance and endothelial dysfunction of the hypertensive state; the inflammatory network and the metalloprotease (MMP)/ tissue inhibitor of metalloprotease (TIMP) system modulate vascular structure and function.. We measured interleukin-6 (IL-6); plasminogen activator inhibitor-1 (PAI-1); tumor necrosis factor-alpha; transforming growth factor-beta; MMP-2, MMP-9, TIMP-1, and TIMP-2 expression; MMP-2 and MMP-9 activity; and TIMP-1 and TIMP-2 protein in adipocytes isolated from paired samples of visceral and subcutaneous adipose tissue of 30 nonobese, untreated hypertensive patients and 20 normotensive controls.. Although expression of IL-6, PAI-1, tumor necrosis factor-alpha, and transforming growth factor-beta were generally higher in visceral adipocytes, IL-6, PAI-1, and tumor necrosis factor-alpha were overexpressed, and transforming growth factor-beta was underexpressed in hypertensive vs. controls (all P<0.0001). These changes were paralleled by higher circulating IL-6 and PAI-1 levels in hypertensive patients. MMP-2 and TIMP-2 expression - which were higher in subcutaneous than visceral cells - were reduced in hypertensive patients (all P<0.0001), whereas MMP-9 and TIMP-1 did not differ between the two groups. Both MMP-2 and MMP-9 activity were reduced in hypertensive patients (all P<0.0001). In the whole dataset, SBP and DBP were directly related to IL-6 and PAI-1 expression and inversely to MMP-2 and MMP-9 activity.. Adipocytes from both visceral and subcutaneous depots of untreated hypertensive patients show a pattern of expression of inflammatory and MMP/TIMP molecules that is compatible with the raised circulating levels of inflammatory markers, is quantitatively related to the height of blood pressure, and provides the cellular basis for the proinflammatory and prothrombotic predisposition of these patients.

Topics: Adipose Tissue; Aged; Biomarkers; Case-Control Studies; Female; Humans; Hypertension; Inflammation; Inflammation Mediators; Interleukin-6; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Middle Aged; Obesity; Plasminogen Activator Inhibitor 1; Subcutaneous Tissue; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

A growing body of evidence suggests that chronic kidney disease is a significant risk for cardiovascular events and stroke regardless of traditional risk factors. The aim of this study was to examine the effects of peroxisome proliferator-activated receptor (PPAR) agonists on the tissue damage affecting salt-loaded spontaneously hypertensive stroke-prone rats ( SHRSPs), an animal model that develops a complex pathology characterized by systemic inflammation, hypertension, and proteinuria and leads to end-organ injury (initially renal and subsequently cerebral). Compared with the PPARγ agonist rosiglitazone, the PPARα ligands fenofibrate and clofibrate significantly increased survival (p < 0.001) by delaying the occurrence of brain lesions monitored by magnetic resonance imaging (p < 0.001) and delaying increased proteinuria (p < 0.001). Fenofibrate completely prevented the renal disorder characterized by severe vascular lesions, tubular damage, and glomerular sclerosis, reduced the number of ED-1-positive cells and collagen accumulation, and decreased the renal expression of interleukin-1β, transforming growth factor β, and monocyte chemoattractant protein 1. It also prevented the plasma and urine accumulation of acute-phase and oxidized proteins, suggesting that the protection induced by PPARα agonists was at least partially caused by their anti-inflammatory and antioxidative properties. The results of this study demonstrate that PPAR agonism has beneficial effects on spontaneous brain and renal damage in SHRSPs by inhibiting systemic inflammation and oxidative stress, and they support carrying out future studies aimed at evaluating the effect of PPARα agonists on proteinuria and clinical outcomes in hypertensive patients with renal disease at increased risk of stroke.

Topics: Animals; Blotting, Western; Brain; Chemokine CCL2; Clofibrate; Disease Models, Animal; Fenofibrate; Hypertension; Inflammation; Interleukin-1beta; Kidney Diseases; Ligands; Male; Oxidative Stress; PPAR alpha; Rats; Rats, Inbred SHR; Stroke; Transforming Growth Factor beta

High salt intake is a known cardiovascular risk factor and is associated with cardiac alterations. To better understand this effect, male Wistar rats were fed a normal (NSD: 1.3% NaCl), high 4 (HSD4: 4%), or high 8 (HSD8: 8%) salt diet from weaning until 18 wk of age. The HSD8 group was subdivided into HSD8, HSD8+HZ (15 mg . kg(-1) . d(-1) hydralazine in the drinking water), and HSD8+LOS (20 mg . kg(-1) . d(-1) losartan in the drinking water) groups. The cardiomyocyte diameter was greater in the HSD4 and HSD8 groups than in the HSD8+LOS and NSD groups. Interstitial fibrosis was greater in the HSD4 and HSD8 groups than in the HSD8+HZ and NSD groups. Hydralazine prevented high blood pressure (BP) and fibrosis, but not cardiomyocyte hypertrophy. Losartan prevented high BP and cardiomyocyte hypertrophy, but not fibrosis. Angiotensin II type 1 receptor (AT(1)) protein expression in both ventricles was greater in the HSD8 group than in the NSD group. Losartan, but not hydralazine, prevented this effect. Compared with the NSD group, the binding of an AT(1) conformation-specific antibody that recognizes the activated form of the receptor was lower in both ventricles in all other groups. Losartan further lowered the binding of the anti-AT(1) antibody in both ventricles compared with all other experimental groups. Angiotensin II was greater in both ventricles in all groups compared with the NSD group. Myocardial structural alterations in response to HSD are independent of the effect on BP. Salt-induced cardiomyocyte hypertrophy and interstitial fibrosis possibly are due to different mechanisms. Evidence from the present study suggests that salt-induced AT(1) receptor internalization is probably due to angiotensin II binding.

Topics: Aldosterone; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Collagen Type I; Collagen Type III; Disease Models, Animal; Drinking; Eating; Echocardiography; Fibrosis; Gene Expression; Heart Ventricles; Hydralazine; Hypertension; Losartan; Male; Myocardium; Potassium; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Renin-Angiotensin System; Sodium; Sodium Chloride, Dietary; Transforming Growth Factor beta; Urine

Remodelling process is associated with activity of such substances as transforming growth factor β1 (TGFβ1), basic fibroblast growth factor (bFGF, FGF2), or insulin like growth factor-1 (IGF-1). In the course of hypertension the remodelling of blood vessels and heart muscle takes place. Studies performed on animal models as well as clinical trials on aetiology of left ventricular hypertrophy (LVH), documented elevated level of both mRNA and proteins of TGFβ1 and IGF-1.. To analyse the correlation between cytokine levels and vascular and LV remodelling.. One hundred seven patients with essential hypertension (age 50 ± 10 years) as well as 50 healthy volunteers participated in the study. Blood pressure was measured in the doctor's office as well as using the ABPM method. The LVH was diagnosed by echocardiographic examination, while ultrasound diagnostic was used to analyse the blood vessels remodelling measured as carotid intima-media thickness. Based on echocardiography results hypertensive patients were divided into two groups - with or without LVH. Peripheral blood concentration of analysed cytokines was measured using Enzyme-Linked Immunosorbent Assay (ELISA). The results were compared with data obtained from control group of normotensive participants.. Values of single measurements of growth factors levels did not show significant differences between analysed groups (p = 0.322), and they did not correlate with the blood pressure levels. The tendency to negative correlation between parameters of diastolic LV function and plasma concentrations of IGF-1 and TGF was found. The value of IMT also did not show significant correlation with TGFβ1, bFGF and IGF-1 in all investigated groups.. The obtained results point to the limited usefulness of single measurements of TGFβ1, bFGF as well as IGF-1 blood concentrations, as the potential prognostic factors of the remodelling of blood vessels and cardiac muscle in patients with essential hypertension.

Topics: Adult; Aged; Blood Vessels; Enzyme-Linked Immunosorbent Assay; Female; Fibroblast Growth Factor 2; Humans; Hypertension; Hypertrophy, Left Ventricular; Insulin-Like Growth Factor I; Male; Middle Aged; Myocardium; Reference Values; Transforming Growth Factor beta; Ventricular Remodeling

Amlodipine, a calcium channel blocker (CCB), is one of the most common antihypertensive medicines in Japan. We evaluated whether the calcium channel blocker confers cardiac protection through the renin-angiotensin-aldosterone system in male stroke-prone spontaneously hypertensive rats (SHR-SP).. Fifteen week-old rats were divided into 2 groups: amlodipine group (3 mg/kg/day, n = 5) and control group (n = 5).. The CCB lowered systolic blood pressure significantly (P < 0.05). Plasma aldosterone concentration in the amlodipine group was remarkably lower than in the control group (P < 0.05), but plasma renin activity and plasma angiotensin II concentration were not different between the two groups. The CCB also suppressed the mRNA expression of brain natriuretic peptide, transforming growth factor-β₁, and fibronectin extracted from the left ventricle.. These results suggest that amlodipine attenuates cardiac damage by lowering plasma aldosterone concentration in hypertensive rats with developing arteriosclerosis.

Topics: Aldosterone; Amlodipine; Angiotensin II; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cardiotonic Agents; Fibronectins; Gene Expression Regulation; Heart; Hypertension; Male; Myocardium; Natriuretic Peptide, Brain; Rats; Rats, Inbred SHR; Renin; Renin-Angiotensin System; Transforming Growth Factor beta

Hypertension and additional non-traditional risk factors can damage the kidney directly and by promoting atherogenesis. Evidence indicates that increased oxidative stress and inflammation may mediate a large part of the effects of risk factors on the kidney. We hypothesized that in hypertensive patients (HT), oxidative stress, measured as 8-ISO-prostaglandin F2alpha (8-ISO-PGF2alpha), should raise paralleling decreasing renal function and should correlate with estimated glomerular filtration rate (eGFR).. In 626 HT with renal function ranging from stages 1 to 5 and 100 healthy controls, plasma levels of 8-ISO-PGF2alpha, high-sensitivity C-reactive protein (CRP), transforming growth factor-beta (TGF-beta) and endothelin-1 (ET-1) were measured. GFR was estimated by the Modification of Diet in Renal Disease study equation.. When HT were stratified according to renal function stages, 8-ISO-PGF2alpha, CRP, TGF-beta and ET-1 increased progressively and significantly with decreasing eGFR. The multiple regression analysis, considering eGFR as a dependent variable, showed that 8-ISO-PGF2alpha (beta = -0.361, P < 0.000001), ET-1 (beta = -0.197, P < 0.0001) and TGF-beta (beta = -0.170, P < 0.0004) correlated independently with eGFR. All biomarkers were good predictors of eGFR <60 ml/min/1.73 m(2) [receiver-operator-curve (ROC) areas]. ET-1 was shown to be the best predictor with a ROC area = 0.938; with a threshold of 4 pg/ml, 91% sensitivity and 85% specificity were observed, whereas 8-ISO had a ROC area = 0.931, and for a threshold of 329 pg/ml, sensitivity and specificity were 89%, respectively. In contrast, CRP showed the lower predictive value with a ROC area = 0.917; with a threshold of 2.52 mg/l, an 87% sensitivity and an 83% specificity were obtained.. Our findings are a clear-cut demonstration of a strong and negative correlation of both oxidative stress and ET-1 with renal function stages in HT. ET-1 and 8-isoprostane are predictive of eGFR.

Topics: Adult; Aged; Atherosclerosis; C-Reactive Protein; Case-Control Studies; Dinoprost; Endothelin-1; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Oxidative Stress; Renal Insufficiency, Chronic; Risk Factors; Transforming Growth Factor beta

Recent studies suggest that expression of the transforming growth factor-beta (TGF-beta)-inducible gene-h3 (betaig-h3) and its anti-lysosomal activity may be responsible for the development of albuminuria and cardiovascular disease associated with hypertension.. We evaluated the proposed linkage using the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat models. The kidney and left ventricular weight/body weight ratios were measured and cardiac collagen deposition was analyzed by Masson's trichrome stain. Renal and cardiac TGF-beta(1) and betaig-h3 expression were determined by real-time reverse transcription-polymerase chain reaction, and renal and cardiac cathepsin B and L activities were measured as an indicator of lysosomal proteolytic activity.. SHR exhibited increased levels of intact urinary albumin without significant change in total albumin (intact plus albumin-derived material) excretion. This was accompanied by renal hypertrophy, increased renal betaig-h3 expression, and reduced renal cathepsin B and L activities. At the same time, increased cardiac TGF-beta(1) and betaig-h3 expression and reduced cardiac cathepsin B activity was identified in SHR in addition to cardiac hypertrophy and increased collagen deposition. All these changes could be ameliorated with ramipril treatment.. These findings implicate for the first time betaig-h3 expression and lysosomal activity as a key factor in the induction of albuminuria and cardiovascular disease associated with hypertension.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiomegaly; Cathepsins; Extracellular Matrix Proteins; Fibrosis; Hypertension; Kidney; Lysosomes; Male; Myocardium; Ramipril; Random Allocation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

A mircoarray analysis was performed to identify novel inflammatory genes that are differentially expressed in the mesenteric arteries of male and female spontaneously hypertensive rats (SHRs). Fractalkine was found to be the inflammatory gene with the greatest differential expression in mesenteric arteries, with the expression being greater in female SHRs compared with males. Greater inflammatory mediators in female SHRs were verified by measuring urinary monocyte chemoattractant protein-1, transforming growth factor-beta, and tumor necrosis factor-alpha (TNF-alpha) excretion, all of which were greater in female SHRs compared with males. Real-time PCR, Western blot analysis, and ELISA verified greater soluble fractalkine in mesenteric arteries of female SHRs. Consistent with increased fractalkine expression, TNF-alpha-converting enzyme and TNF-alpha levels in mesenteric arteries were also greater in female SHRs. We next tested the hypothesis that mesenteric arteries from female SHRs will have greater fractalkine-induced dysfunction. Acetylcholine, sodium nitroprusside, phenylephrine, and KCl concentration-response curves were performed in third-order mesenteric arteries from male and female SHRs pretreated with either vehicle or fractalkine (1 microg/ml). Fractalkine decreased sensitivity to 1) acetylcholine in arteries from male SHRs, 2) phenylephrine in arteries from both sexes, and 3) KCl in arteries from female SHRs. In conclusion, urinary and vascular markers of inflammation are greater in female SHRs compared with males, although blood pressure and cardiovascular risk are less in females.

Topics: Acetylcholine; Animals; Chemokine CCL2; Chemokine CX3CL1; Disease Models, Animal; Female; Hypertension; Male; Mesenteric Arteries; Nitroprusside; Phenylephrine; Potassium Chloride; Rats; Rats, Inbred SHR; Sex Characteristics; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vasodilator Agents

Significant reduction of renal mass causes progressive deterioration of renal function and structure which is mediated by systemic and glomerular hypertension, hyperfiltration, oxidative stress, inflammation, and dyslipidemia. Niacin is known to improve lipid metabolism and exert antioxidant/anti-inflammatory actions. Therefore, we considered that niacin supplementation may attenuate oxidative stress, inflammation, and tissue injury in the remnant kidney. To this end, 56 nephrectomized [chronic kidney disease (CKD)] rats were randomly assigned to niacin-treated (50 mg x kg(-1) x day(-1) in the drinking water for 12 wk) and untreated groups. Sham-operated rats served as controls. The untreated CKD rats exhibited azotemia, hypertension, hypertriglyceridemia, proteinuria, glomerulosclerosis, tubulointerstitial damage, upregulation of MCP-1, plasminogen activator inhibitor-1 (PAI-1), transforming growth factor (TGF)-beta, cyclooxygenase (COX)-1, COX-2, and NAD(P)H oxidase (NOX-4, gp91(phox), p47(phox) and p22(phox) subunits) and activation of NF-kappaB (IkappaB phosphorylation). Niacin administration reduced MCP-1, PAI-1, TGF-beta, p47(phox), p22(phox), COX-1, and NF-kappaB activation, ameliorated hypertension, proteinuria, glomerulosclerosis, and tubulointerstitial injury. Although niacin lowered serum creatinine and raised creatinine clearance, the differences did not reach statistical significance. Thus niacin supplementation helps to attenuate histological injury and mitigate upregulation of oxidative and inflammatory systems in the remnant kidney.

Topics: Animals; Chemokine CCL2; Creatinine; Disease Models, Animal; Hypertension; Inflammation; Kidney Failure, Chronic; Male; Nephrectomy; NF-kappa B; Niacin; Oxidative Stress; Plasminogen Activator Inhibitor 1; Proteinuria; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Vitamin B Complex

In hypertension, elevated levels of oxidative/inflammatory mediators including nuclear factor kappaB (NF-kappaB), activating protein (AP-1), c-Jun-NH2-terminal kinase (JNK), and cell-regulatory proteins such as transforming growth factor beta (TGF-beta), trigger the mobilization of extracellular matrix (ECM) leading to fibrosis, hypertrophy and impairment of cardiac function. Although the heme oxygenase (HO) system is cytoprotective, its effects on cardiac fibrosis and hypertrophy in deoxycorticosterone acetate (DOCA-salt) hypertension are not completely elucidated. Here, we report cardioprotection by the HO inducer, heme arginate against histopathological lesions in DOCA-hypertension. Treatment with heme arginate restored physiological blood pressure, and abated cardiac hypertrophy (3.75 +/- 0.12 vs. 3.19 +/- 0.09 g/kg body wt; n =16, P < 0.01), left-to-right ventricular ratio (6.67 +/- 0.62 vs. 4.39 +/- 0.63; n = 16, P < 0.01), left ventricular mass (2.48 +/- 0.14 vs. 2.01 +/- 0.09 g/kg body wt; n = 16, P < 0.01) and left-ventricular wall thickness (2.82 +/- 0.16 vs. 1.98 +/- 0.14 mm; n = 16, P < 0.01), whereas the HO inhibitor, chromium mesoporphyrin, exacerbated hypertrophy and cardiac lesions. The suppression of cardiac hypertrophy was accompanied by a robust increase in HO-1, HO activity, cyclic guanosine monophosphate (cGMP), ferritin and the total antioxidant capacity, whereas 8-isoprostane, NF-kappaB, JNK, AP-1, TGF-beta, fibronectin and collagen-I were significantly abated. Correspondingly, histopathological parameters that depict progressive cardiac damage, including fibrosis, interstitial/perivascular collagen deposition, scarring, muscle-fiber thickness, muscular hypertrophy and coronary-arteriolar thickening were abated. Our study suggests that upregulating the HO system lowers blood pressure, potentiates the antioxidant status in tissues, suppresses oxidative stress/mediators such as NF-kappaB, AP-1 and cJNK, and suppresses the mobilization of ECM proteins like TGF-beta, collagen and fibronectin, with corresponding reduction of cardiac histopathological lesion and hypertrophy.

Topics: Animals; Arginine; Cardiomegaly; Desoxycorticosterone; Disease Models, Animal; Heart; Heart Diseases; Heme; Heme Oxygenase (Decyclizing); Hypertension; Hypertrophy, Left Ventricular; Male; MAP Kinase Kinase 4; Mesoporphyrins; Myocardium; NF-kappa B; Rats; Rats, Sprague-Dawley; Transcription Factor AP-1; Transforming Growth Factor beta

The lymphocyte migration inhibitor FTY720 attenuates experimental hypertensive nephropathy. Infiltration with lymphocytes is found in both immune and nonimmune chronic kidney diseases. In a rat model of immune-initiated progressive glomerulosclerosis, selective inhibition of lymphocyte infiltration by FTY720 showed significant beneficial effects on renal fibrosis. To test whether this translates into hypertensive nephropathy (HN), the lymphocyte migration inhibitor was administered to rats following nephrectomy. Two days after surgery, male Wistar rats were allocated to the following groups: Sham surgery, nephrectomy (HN), and HN + FTY720 (0.3 mg/kg body wt). Therapy was continued for 6 wk. Treatment with FTY720 was found to selectively reduce blood lymphocyte counts by 85% (P < 0.001 vs. HN) and renal lymphocyte infiltration (CD-3 positive cells) by 63% (P < 0.01 vs. HN) as was anticipated. Lymphocyte depletion went along with a significant reduction in proteinuria (-28%), whereas hypertensive systemic blood pressure remained unchanged (160 +/- 5 vs. 161 +/- 5 mmHg, P = not significant). The markedly increased histological tubulointerstitial and glomerular matrix protein accumulation, collagen, laminin, and fibronectin deposition were all significantly impeded in the FTY720-treated animals. The anti-fibrotic effects of FTY720 were paralleled by significant reductions in renal transforming growth factor (TGF)-beta overexpression, macrophage infiltration, and cell proliferation. In conclusion, the lymphocyte migration inhibitor FTY720 significantly limits histological and molecular fibrosis in a model of hypertensive nephropathy without affecting increased systemic blood pressure. Prevention of renal lymphocytes' infiltration by FTY720 was followed by significant reductions in TGF-beta overexpression, macrophage infiltration, and renal cell proliferation. These results suggest that infiltrating lymphocytes play an active, profibrotic role in the progression of hypertensive renal tissue injury.

Topics: Animals; Blood Pressure; Cell Movement; Cell Proliferation; Disease Models, Animal; Extracellular Matrix; Fibrosis; Fingolimod Hydrochloride; Hypertension; Immunosuppressive Agents; Kidney; Kidney Diseases; Lymphocytes; Macrophages; Male; Nephrectomy; Propylene Glycols; Proteinuria; Rats; Rats, Wistar; Sphingosine; Transforming Growth Factor beta

Primary aldosteronism (PA) is the most common secondary cause of hypertension that has recently been implicated in alterations of the immune system and progression of cardiovascular disease.. To study the cytokines transforming growth factor beta1 (TGF-beta1), tumor necrosis factor alpha (TNF-alpha), and interleukin 10 (IL-10) in patients with PA and essential hypertensives (EH) and evaluate its association with the renin-angiotensin-aldosterone system.. We studied 26 PA and 52 EH patients as controls, adjusted by their blood pressure, body mass index, age, and gender. In both groups, PA and EH, we measured serum aldosterone (SA), plasma renin activity (PRA), and cytokines TGF- beta1, TNF-alpha, and IL-10. In addition, 17 PA patients were treated for 6 months with spironolactone, a mineralocorticoid receptor (MR) antagonist.. PA patients had lower levels of TGF-beta1 (17.6+/-4.1 vs 34.5+/-20.5 pg/ml, p<0.001) and TNF-alpha (17.0+/-4.4 vs 35.6+/-21.7 pg/ml, p<0.001) and similar IL-10 levels (99.7+/-18.7 vs 89.4+/-49.5 pg/ml, p: ns), as compared with EH controls. TGF-beta1 and TNF-alpha levels showed a remarkable correlation with SA/PRA ratio in the total group (PA+EH). The treatment of PA patients with spironolactone increased the TGF-beta1 levels (18.3+/-5.9 to 28.4+/-6.3 pg/ml, p<0.001), while TNF-alpha, and IL-10 remained unchanged.. Our results showed that PA patients have lower TGF-beta1 and TNF-alpha cytokine serum levels than EH. TGF-beta1 levels were restored with spironolactone, showing a MR-dependent regulation. In this way, the chronic aldosterone excess modifies the TGF-beta1 levels, which could produce an imbalance in the immune system homeostasis that may promote an early proinflammatory cardiovascular phenotype.

Topics: Adult; Aldosterone; Cross-Sectional Studies; Female; Humans; Hyperaldosteronism; Hypertension; Interleukin-10; Male; Middle Aged; Renin; Renin-Angiotensin System; Spironolactone; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Metabolic syndrome (MS) is an independent risk factor for chronic kidney diseases. As the renin-angiotensin system (RAS) is known to have a key role in renal damage, blockade of RAS may show renoprotective effects in MS. In this study, we investigated the renoprotective effects and mechanisms of action of an angiotensin receptor blocker (ARB) in spontaneously hypertensive (SHR/NDmcr-cp) rats as a model of MS. Male SHR/NDmcr-cp rats at 9 weeks of age were divided into three groups, each of which was treated for 12 weeks with vehicle, hydralazine (7.5 mg kg(-1) per day, p.o.) or ARB (olmesartan, 5 mg kg(-1) per day, p.o.). Blood pressure and urinary protein (UP) excretion were monitored. Kidney tissues were subjected to histological, immunohistochemical and molecular analyses. UP excretion increased with age in vehicle-treated SHR/NDmcr-cp rats compared with that in age-matched WKY/Izm rats. In addition, there was significant glomerular damage (increased glomerular sclerosis index, desmin staining and proliferating cell nuclear antigen (PCNA)-positive cells, electron microscopic findings of podocyte injury) and tubulointerstitial damage (increased tubulointerstitial fibrosis index, type IV collagen staining, PCNA-positive cells and expression of TGF-beta mRNA) in vehicle-treated SHR/NDmcr-cp rats compared with that in control rats. All the findings that related to glomerular and tubulointerstitial damage were significantly improved by ARB. Hydralazine mitigated the observed renal damage but was much less effective than ARB, despite similar decreases in blood pressure. There were no significant differences in glucose and lipid metabolism among vehicle-treated, hydralazine-treated and ARB-treated SHR/NDmcr-cp animals. These data suggest that RAS is deeply involved in the pathogenesis of renal damage in MS, and ARBs could provide a powerful renoprotective regimen for patients with MS.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Biomarkers; Blood Pressure; Body Weight; Hypertension; Immunohistochemistry; Kidney; Kidney Diseases; Kidney Function Tests; Kidney Glomerulus; Male; Metabolic Diseases; Microscopy, Electron, Transmission; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Sclerosis; Transforming Growth Factor beta

Connective tissue growth factor (CTGF) plays a critical role in angiotensin II (Ang II)-mediated hypertensive nephropathy. The present study investigated the mechanisms and specific roles of individual Smads in Ang II-induced CTGF and collagen I expression in tubular epithelial cells with deletion of transforming growth factor (TGF)-beta1, overexpression of Smad7, or knockdown of Smad2 or Smad3. We found that Ang II-induced tubular CTGF and collagen I mRNA and protein expressions were regulated positively by phosphorylated Smad2/3 but negatively by Smad7 because overexpression of Smad7-abolished Ang II-induced Smad2/3 phosphorylation and upregulation of CTGF and collagen I in vitro and in a rat model of remnant kidney disease. Additional studies revealed that, in addition to a late (24-hour) TGF-beta-dependent Smad2/3 activation, Ang II also induced a rapid activation of Smad2/3 at 15 minutes and expression of CTGF and collagen I in tubular epithelial cells lacking the TGF-beta gene, which was blocked by the addition of an Ang II type 1 receptor antagonist (losartan) and inhibitors to extracellular signal-regulated kinase 1/2 (PD98059) and p38 (SB203580) but not by inhibitors to Ang II type 2 receptor (PD123319) or c-Jun N-terminal kinase (SP600125), demonstrating a TGF-beta-independent, Ang II type 1 receptor-mediated extracellular signal-regulated kinase/p38 mitogen-activated protein kinase cross-talk pathway in Ang II-mediated CTGF and collagen I expression. Importantly, the ability of knockdown of Smad3, but not Smad2, to inhibit Ang II-induced CTGF and collagen I expression further revealed an essential role for Smad3 in Ang II-mediated renal fibrosis. In conclusion, Ang II induces tubular CTGF expression and renal fibrosis via the TGF-beta-dependent and -independent Smad3 signaling pathways, suggesting that targeting Smad3 may have therapeutic potential for hypertensive nephropathy.

Topics: Angiotensin II; Animals; Cell Line; Collagen Type I; Connective Tissue Growth Factor; Disease Models, Animal; Epithelial Cells; Hypertension; Kidney Diseases; Kidney Tubules; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; Rats, Sprague-Dawley; Signal Transduction; Smad2 Protein; Smad3 Protein; Smad7 Protein; Transforming Growth Factor beta; Up-Regulation

Hypertensive patients with large blood pressure variability (BPV) have aggravated end-organ damage. However, the pathogenesis remains unknown. We investigated whether exaggerated BPV aggravates hypertensive cardiac remodeling and function by activating inflammation and angiotensin II-mediated mechanisms. A model of exaggerated BPV superimposed on chronic hypertension was created by performing bilateral sinoaortic denervation (SAD) in spontaneously hypertensive rats (SHRs). SAD increased BPV to a similar extent in Wistar Kyoto rats and SHRs without significant changes in mean blood pressure. SAD aggravated left ventricular and myocyte hypertrophy and myocardial fibrosis to a greater extent and impaired left ventricular systolic function in SHRs. SAD induced monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen mRNA upregulations and macrophage infiltration of the heart in SHRs. The effects of SAD on cardiac remodeling and inflammation were much smaller in Wistar Kyoto rats compared with SHRs. Circulating levels of norepinephrine, the active form of renin, and inflammatory cytokines were not affected by SAD in Wistar Kyoto rats and SHRs. A subdepressor dose of candesartan abolished the SAD-induced left ventricular/myocyte hypertrophy, myocardial fibrosis, macrophage infiltration, and inductions of monocyte chemoattractant protein-1, transforming growth factor-beta, and angiotensinogen and subsequently prevented systolic dysfunction in SHRs with SAD. These findings suggest that exaggerated BPV induces chronic myocardial inflammation and thereby aggravates cardiac remodeling and systolic function in hypertensive hearts. The cardiac angiotensin II system may play a role in the pathogenesis of cardiac remodeling and dysfunction induced by a combination of hypertension and exaggerated BPV.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chemokine CCL2; Chronic Disease; Disease Models, Animal; Heart Diseases; Heart Ventricles; Hypertension; Hypertrophy; Inflammation; Macrophages; Male; Myocytes, Cardiac; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrazoles; Transforming Growth Factor beta; Ventricular Remodeling

A porcine aortic coarctation model was used to examine regulation of gene expression in early hypertensive vascular remodeling. Aortic segments were collected proximal (high pressure) and distal (low pressure) to the coarctation after 2 wk of sustained hypertension (mean arterial pressure>150 mmHg). Porcine 10K oligoarrays used for gene expression profiling of the two regions of aorta revealed downregulation of cytoskeletal and upregulation of extracellular region genes relative to the whole genome. A genomic database search for transforming growth factor-beta (TGF-beta) control elements showed that 19% of the genes that changed expression due to hypertension contained putative TGF-beta control elements. Real-time RT-PCR and microarray analysis showed no change in expression of TGF-beta1, TGF-beta2, TGF-beta3, or bone morphogenetic proteins-2 and -4, yet immunohistochemical staining for phosphorylated SMAD2, an indicator of TGF-beta signaling, and for phosphorylated SMAD1/5/8, an indicator of signaling through the bone morphogenetic proteins, showed the highest percentage of positively stained cells in the proximal aortic segments of occluded animals. For TGF-beta signaling, this increase was significantly different than for sham-operated controls. Western blot analysis showed no difference in total TGF-beta1 protein levels with respect to treatment or aortic segment. Immunohistochemistry showed that the protein levels of latency-associated peptide was decreased in proximal segments of occluded animals. Collectively, these results suggest that activation of TGF-beta, but not altered expression, may be a major mechanism regulating early hypertensive vascular remodeling.

Topics: Animals; Aorta; Aortic Coarctation; Blotting, Western; Bone Morphogenetic Proteins; Cell Differentiation; Databases, Genetic; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation; Hypertension; Immunohistochemistry; Muscle, Smooth, Vascular; Oligonucleotide Array Sequence Analysis; Phosphorylation; Polymerase Chain Reaction; Regional Blood Flow; Signal Transduction; Smad Proteins; Swine; Swine, Miniature; Transforming Growth Factor beta; Ultrasonography, Doppler, Color

Human and animal studies demonstrate an untoward effect of excess dietary NaCl (salt) intake on cardiovascular function and life span. The endothelium in particular augments the production of transforming growth factor (TGF)-beta, a fibrogenic growth factor, in response to excess dietary salt intake. This study explored the initiating mechanism that regulates salt-induced endothelial cell production of TGF-beta. Male Sprague-Dawley rats were given diets containing different amounts of NaCl and potassium for 4 days. A bioassay for TGF-beta demonstrated increased (35.2%) amounts of active TGF-beta in the medium of aortic ring segments from rats on the high-salt diet compared with rats maintained on a 0.3% NaCl diet. Inhibition of the large-conductance, calcium-activated potassium channel inhibited dietary salt-induced vascular production of TGF-beta but did not affect production of TGF-beta by ring segments from rats on the low-salt diet. Immunohistochemical and Western analyses demonstrated the alpha subunit of the calcium-activated potassium channel in endothelial cells. Increasing medium [K+] inhibited production of dietary salt-induced vascular production levels of total and active TGF-beta but did not alter TGF-beta production by aortic rings from rats on the 0.3% NaCl diet. Increasing dietary potassium content decreased urinary active TGF-beta in animals receiving the high-salt diet but did not change urinary active TGF-beta in animals receiving the low-salt diet. The findings demonstrated an interesting interaction between the dietary intake of potassium and excess NaCl and further showed the fundamental role of the endothelial calcium-activated potassium channel in the vascular response to excess salt intake.

Topics: Animals; Blotting, Western; Disease Models, Animal; Endothelium, Vascular; Hypertension; Immunohistochemistry; Male; Muscle, Smooth, Vascular; Potassium; Probability; Random Allocation; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Sodium Chloride, Dietary; Transforming Growth Factor beta

The aim of the present study was to test the hypothesis that elevation of prorenin in plasma is sufficient to induce cardiac fibrosis. Normotensive cyp1a1ren-2 transgenic rats with normal plasma prorenin and aldosterone levels were given 0.125% indole-3-carbinol (I3C) orally for a period of 12 wk. Plasma prorenin and aldosterone levels were determined in 4-wk intervals, and cardiac marker enzymes for hypertrophy, fibrosis, and oxidative stress as well as cardiac pathology were investigated. In I3C-treated cyp1a1 ren-2 transgenic rats, plasma prorenin concentrations were >100-fold elevated (> or = 7.1 + or - 2.6 microg ANG I.ml(-1).h(-1) vs. < or = 0.07 + or - 0.1; P < 0.001), whereas active renin levels were suppressed (0.09 + or - 0.02 vs. 0.2 + or - 0.1; P < 0.05). Aldosterone concentrations were elevated three- to fourfold for a period of >4 wk (574 + or - 51 vs. 160 + or - 68 pg/ml; P < 0.01). After 12 wk of I3C, rats exhibited moderate cardiac hypertrophy (heart weight/body weight 2.5 + or - 0.04 vs. 3.1 + or - 0.1 mg/g; P < 0.01). There was a slight increase in mRNA contents of endothelin 1 (1.21 + or - 0.08 vs. 0.75 + or - 0.007; P < 0.001), NADP oxidase-2 (1.03 + or - 0.006 vs. 0.76 + or - 0.04; P < 0.001), transforming growth factor-beta (0.99 + or - 0.06 vs. 0.84 + or - 0.04; P < 0.05), collagen type I (1.32 + or - 0.32 vs. 0.94 + or - 0.18; P < 0.05), and intercellular adhesion molecule-1 (1.12 + or - 0.12 vs. 0.84 + or - 0.08; P < 0.05). These genes are known to be stimulated by the renin-angiotensin system. There were no histological signs of fibrosis in the heart. We found that prorenin and aldosterone alone are not sufficient to induce considerable cardiac fibrosis in the absence of sodium load.

Topics: Administration, Oral; Aldosterone; Animals; Cardiomegaly; Collagen Type I; Cytochrome P-450 CYP1A1; Disease Models, Animal; Endothelin-1; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Hyperaldosteronism; Hypertension; Indoles; Intercellular Adhesion Molecule-1; Magnetic Resonance Imaging; Membrane Glycoproteins; Mice; Myocardium; NADPH Oxidase 2; NADPH Oxidases; Phosphorylation; Promoter Regions, Genetic; Rats; Rats, Inbred F344; Rats, Transgenic; Renin; RNA, Messenger; Time Factors; Transforming Growth Factor beta

Whether a high plasma aldosterone concentration induced by strict salt restriction promotes cardiac remodeling remains controversial. Male Sprague-Dawley rats at 10weeks of age were given normal salt (NS) (1.5% NaCl) or low salt (LS) (0.05% NaCl) diets. Each animal underwent aortocaval fistula creation for volume-overloaded heart failure or sham surgery. All rats with a fistula received either vehicle or a non-hypotensive dose of spironolactone (200mg/kg/day) by gavage. Two weeks later, the LS diet significantly increased the plasma aldosterone level in the sham-operated and fistula-created rats (2677+/-662pg/ml and 2406+/-422pg/ml) compared with that in rats given the NS diet (518+/-18pg/ml and 362+/-45pg/ml, respectively). In sham-operated rats, the difference in plasma aldosterone level did not affect the extent of myocardial fibrosis (1.8+/-0.1% with LS diet vs. 1.5+/-0.3% with NS diet). However, the increase in myocardial fibrosis in fistula-created rats was more prominent with the LS diet than with the NS diet (4.7+/-0.3% vs. 3.4+/-0.1%). In addition, the fistula-created rats on the LS diet expressed significantly increased oxidative stress and transforming growth factor-beta compared with those on the NS diets (P<0.05). These increases in the fistula-created rats on the LS diet were significantly suppressed by the non-hypotensive dose of spironolactone (P<0.05). These results suggest that increased plasma aldosterone level with strict salt restriction activated the mineralocorticoid receptor signaling in volume-overloaded condition, resulting in increased myocardial fibrosis.

Topics: Aldosterone; Animals; Atrial Natriuretic Factor; Body Weight; Cell Size; Contraindications; Diet, Sodium-Restricted; Endomyocardial Fibrosis; Heart; Heart Failure; Hemodynamics; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Organ Size; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Signal Transduction; Spironolactone; Transforming Growth Factor beta; Tyrosine; Ventricular Remodeling

Mechanical forces are potent modulators of the growth and hypertrophy of vascular cells. We examined the molecular mechanisms through which mechanical force and hypertension modulate endothelial cell regulation of vascular homeostasis. Exposure to mechanical strain increased the paracrine inhibition of vascular smooth muscle cells (VSMCs) by endothelial cells. Mechanical strain stimulated the production of perlecan and heparan sulfate glycosaminoglycans by endothelial cells. By inhibiting the expression of perlecan with an antisense vector we demonstrated that perlecan was essential to the strain-mediated effects on endothelial cell growth control. Mechanical regulation of perlecan expression in endothelial cells was governed by a mechanotransduction pathway requiring autocrine transforming growth factor beta (TGF-beta) signaling and intracellular signaling through the ERK pathway. Immunohistochemical staining of the aortae of spontaneously hypertensive rats demonstrated strong correlations between endothelial TGF-beta, phosphorylated signaling intermediates, and arterial thickening. Further, studies on ex vivo arteries exposed to varying levels of pressure demonstrated that ERK and TGF-beta signaling were required for pressure-induced upregulation of endothelial HSPG. Our findings suggest a novel feedback control mechanism in which net arterial remodeling to hemodynamic forces is controlled by a dynamic interplay between growth stimulatory signals from VSMCs and growth inhibitory signals from endothelial cells.

Topics: Animals; Autocrine Communication; Blood Vessels; Cell Communication; Endothelial Cells; Endothelium, Vascular; Humans; Hypertension; Mechanotransduction, Cellular; Rats; Rats, Inbred SHR; Stress, Mechanical; Transforming Growth Factor beta

Hypertension induces dysfunctional matrix remodeling that results in the development of myocardial fibrosis. Myocardial fibrosis adversely affects compliance, electrical activity and cardiac function in patients with hypertensive heart disease. Matrix metalloproteinases (MMPs) are a class of enzymes that regulate the remodeling of the matrix in response to pressure overload. Several studies have shown that the MMP-1/TIMP (tissue inhibitor of matrix metalloproteinase) ratio is decreased in hypertensive heart disease. However, the exact role that MMP-1 has in modulating the fibrotic response to hypertension is largely unknown. We hypothesized that cardiac expression of MMP-1 in mice would protect against the development of dysfunctional matrix remodeling during pressure overload. To investigate this, a suprarenal aortic banding model was utilized. Banded and unbanded MMP-1 transgenic mice were compared with appropriately matched wild-type mice. The banded mice were examined at 2 and 5 weeks after banding. MMP-1 attenuated the development of cardiac fibrosis, prevented left ventricular dilation and preserved cardiac function in mice that were exposed to pressure overload. Thus, MMP-1 protected the heart from the dysfunctional remodeling that occurs in response to chronic hypertension. In conclusion, these results suggest that strategies aimed at improving the MMP-1/TIMP balance in the myocardium may help to prevent the onset and progression of hypertensive heart disease.

Topics: Animals; Aorta, Abdominal; Disease Models, Animal; Fibrosis; Gene Expression Regulation, Enzymologic; Heart Failure; Hypertension; Male; Matrix Metalloproteinase 1; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Myocardium; Systole; Transforming Growth Factor beta; Ventricular Remodeling

This study was designed to investigate whether chronic angiotensin II type 1 receptor blockade inhibits ventricular interstitial fibrosis with the induction of programmed cell death (apoptosis) in prolonged nitric oxide synthase (NOS) inhibition using N(G)-nitro-l-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHR). Four groups of 20-week-old male SHR were studied for 3 weeks: the control group; the L-NAME group given 80 mg/L L-NAME in drinking water; and the groups given 1 or 30 mg/(kg day) of valsartan, respectively, with L-NAME. The L-NAME group showed marked cardiac tissue injuries with elevated blood pressure such as interstitial fibrosis, intimal thickening of small arteries, and myocardial necrosis. Caspase-3, an apoptosis inducer, immunoreactivity was increased in interstitial cells, and the tissue RNA expression of transforming growth factor-ß(1) (TGF-ß(1)) was also increased in the L-NAME group. Low-dose valsartan treatment did not affect blood pressure or cardiac weight but alleviated the L-NAME-induced interstitial fibrosis with increased mRNA level of caspase-3 in interstitial fibroblasts. High-dose valsartan significantly lowered blood pressure and decreased the mRNA levels of caspase-3 and TGF-ß(1). These data suggest that low-dose valsartan inhibits interstitial fibrosis by promoting apoptosis of the fibroblasts without blood pressure changes, which may provide the TGF-ß(1) inhibition in the development of interstitial fibrosis in severe hypertension rat model.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Apoptosis; Caspase 3; Fibrosis; Hypertension; Male; Myocardium; NG-Nitroarginine Methyl Ester; Rats; Rats, Inbred SHR; RNA; Tetrazoles; Transforming Growth Factor beta; Valine; Valsartan; Ventricular Remodeling

Chronic renal hypoxia is suspected to play a pathogenic role in the genesis of diabetic nephropathy (DN). Cobalt enhances the activity of the hypoxia-inducible factor (HIF), a key factor in the defence against hypoxia. Its long-term effect on DN is evaluated.. Cobalt chloride was given to hypertensive, type 2 diabetic rats with nephropathy (SHR/NDmcr-cp). Treatment was initiated at the age of 13 weeks and continued for 26 weeks.. Cobalt did not correct hypertension and metabolic abnormalities (obesity, hyperglycaemia and hyperlipidaemia) but reduced proteinuria as well as histological kidney injury. Cobalt upregulated renal HIF-1alpha and HIF-2alpha expression and increased the expression of HIF-regulated genes, including erythropoietin, vascular endothelial growth factor and heme oxygenase-1. The renal expression of transforming growth factor (TGF)-beta and connective tissue growth factor (CTGF) was significantly reduced by cobalt. The renal expression of NADPH oxidase, a marker of oxidative stress, and the renal content of pentosidine, a marker of advanced glycation, were also significantly reduced by cobalt.. Cobalt achieved renal protection independently of metabolic status and blood pressure. Its effect was attributed to the upregulation of HIF and HIF-regulated genes and to a mitigated advanced glycation and oxidative stress.

Topics: Animals; Antimutagenic Agents; Arginine; Basic Helix-Loop-Helix Transcription Factors; Blood Pressure; Blotting, Western; Chromatography, High Pressure Liquid; Cobalt; Connective Tissue Growth Factor; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Gene Expression; Glycation End Products, Advanced; Hypertension; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immediate-Early Proteins; Insulin-Like Growth Factor Binding Proteins; Intercellular Signaling Peptides and Proteins; Kidney; Lysine; Male; NADPH Oxidases; Obesity; Oxidative Stress; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; RNA, Messenger; Transforming Growth Factor beta

The progressive deterioration of renal function and structure resulting from renal mass reduction are mediated by a variety of mechanisms, including oxidative stress and inflammation. Melatonin, the major product of the pineal gland, has potent_antioxidant and anti-inflammatory properties, and its production is impaired in chronic renal failure. We therefore investigated if melatonin treatment would modify the course of chronic renal failure in the remnant kidney model. We studied rats followed 12 wk after renal ablation untreated (Nx group, n = 7) and treated with melatonin administered in the drinking water (10 mg/100 ml) (Nx + MEL group, n = 8). Sham-operated rats (n = 10) were used as controls. Melatonin administration increased 13-15 times the endogenous hormone levels. Rats in the Nx + MEL group had reduced oxidative stress (malondialdehyde levels in plasma and in the remnant kidney as well as nitrotyrosine renal abundance) and renal inflammation (p65 nuclear factor-kappaB-positive renal interstitial cells and infiltration of lymphocytes and macrophages). Collagen, alpha-smooth muscle actin, and transforming growth factor-beta renal abundance were all increased in the remnant kidney of the untreated rats and were reduced significantly by melatonin treatment. Deterioration of renal function (plasma creatinine and proteinuria) and structure (glomerulosclerosis and tubulointerstitial damage) resulting from renal ablation were ameliorated significantly with melatonin treatment. In conclusion, melatonin administration improves the course of chronic renal failure in rats with renal mass reduction. Further studies are necessary to define the potential usefulness of this treatment in other animal models and in patients with chronic renal disease.

Topics: Actins; Animals; Blood Pressure; Cell Movement; Collagen Type IV; Creatinine; Disease Models, Animal; Hypertension; Hypertrophy; Inflammation; Kidney; Kidney Failure, Chronic; Leukocytes; Male; Malondialdehyde; Melatonin; Nephrectomy; Oxidative Stress; Proteinuria; Rats; Rats, Sprague-Dawley; Transcription Factor RelA; Transforming Growth Factor beta; Tyrosine

Activation of the renin-angiotensin system contributes to the progression of chronic kidney disease. Based on the known cellular effects of ANG II to promote inflammation, we posited that stimulation of lymphocyte responses by ANG II might contribute to the pathogenesis of hypertensive kidney injury. We therefore examined the effects of the immunosuppressive agent mycophenolate mofetil (MMF) on the course of hypertension and kidney disease induced by chronic infusion of ANG II in 129/SvEv mice. Although it had no effect on the severity of hypertension or cardiac hypertrophy, treatment with MMF significantly reduced albuminuria and ameliorated kidney injury, decreasing glomerulosclerosis and reducing lymphocyte infiltration into the renal interstitium. Attenuation of renal pathology with MMF was associated with reduced expression of mRNAs for the proinflammatory cytokines interferon-gamma and tumor necrosis factor-alpha and the profibrotic cytokine transforming growth factor-beta. As infiltration of the kidney by T lymphocytes was a prominent feature of ANG II-dependent renal injury, we carried out experiments examining the effects of ANG II on lymphocytes in vitro. We find that exposure of splenic lymphocytes to ANG II causes prominent rearrangements of the actin cytoskeleton. These actions require the activity of Rho kinase. Thus, ANG II exaggerates hypertensive kidney injury by stimulating lymphocyte responses. These proinflammatory actions of ANG II seem to have a proclivity for inducing kidney injury while having negligible actions in the pathogenesis of cardiac hypertrophy.

Topics: Albuminuria; Angiotensin II; Animals; Cardiomegaly; Cell Proliferation; Cytoskeleton; Disease Models, Animal; Hypertension; Immunosuppressive Agents; Interferon-gamma; Kidney Diseases; Male; Mice; Mice, Knockout; Mycophenolic Acid; Sodium Chloride, Dietary; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vasoconstrictor Agents

Cardiac remodeling, which typically results from chronic hypertension or following an acute myocardial infarction, is a major risk factor for the development of heart failure and, ultimately, death. The renin-angiotensin system (RAS) has previously been established to play an important role in the progression of cardiac remodeling, and inhibition of a hyperactive RAS provides protection from cardiac remodeling and subsequent heart failure. Our previous studies have demonstrated that overexpression of angiotensin-converting enzyme 2 (ACE2) prevents cardiac remodeling and hypertrophy during chronic infusion of angiotensin II (ANG II). This, coupled with the knowledge that ACE2 is a key enzyme in the formation of ANG-(1-7), led us to hypothesize that chronic infusion of ANG-(1-7) would prevent cardiac remodeling induced by chronic infusion of ANG II. Infusion of ANG II into adult Sprague-Dawley rats resulted in significantly increased blood pressure, myocyte hypertrophy, and midmyocardial interstitial fibrosis. Coinfusion of ANG-(1-7) resulted in significant attenuations of myocyte hypertrophy and interstitial fibrosis, without significant effects on blood pressure. In a subgroup of animals also administered [d-Ala(7)]-ANG-(1-7) (A779), an antagonist to the reported receptor for ANG-(1-7), there was a tendency to attenuate the antiremodeling effects of ANG-(1-7). Chronic infusion of ANG II, with or without coinfusion of ANG-(1-7), had no effect on ANG II type 1 or type 2 receptor binding in cardiac tissue. Together, these findings indicate an antiremodeling role for ANG-(1-7) in cardiac tissue, which is not mediated through modulation of blood pressure or altered cardiac angiotensin receptor populations and may be at least partially mediated through an ANG-(1-7) receptor.

Topics: Analysis of Variance; Angiotensin I; Angiotensin II; Animals; Blood Pressure; Cardiomegaly; Disease Models, Animal; Fibrosis; Heart; Hypertension; Male; Myocardium; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, G-Protein-Coupled; Time Factors; Transforming Growth Factor beta; Ventricular Remodeling

Activin and myostatin are related members of the TGF-beta growth factor superfamily. FSTL3 (Follistatin-like 3) is an activin and myostatin antagonist whose physiological role in adults remains to be determined. We found that homozygous FSTL3 knockout adults developed a distinct group of metabolic phenotypes, including increased pancreatic islet number and size, beta cell hyperplasia, decreased visceral fat mass, improved glucose tolerance, and enhanced insulin sensitivity, changes that might benefit obese, insulin-resistant patients. The mice also developed hepatic steatosis and mild hypertension but exhibited no alteration of muscle or body weight. This combination of phenotypes appears to arise from increased activin and myostatin bioactivity in specific tissues resulting from the absence of the FSTL3 antagonist. Thus, the enlarged islets and beta cell number likely result from increased activin action. Reduced visceral fat is consistent with a role for increased myostatin action in regulating fat deposition, which, in turn, may be partly responsible for the enhanced glucose tolerance and insulin sensitivity. Our results demonstrate that FSTL3 regulation of activin and myostatin is critical for normal adult metabolic homeostasis, suggesting that pharmacological manipulation of FSTL3 activity might simultaneously reduce visceral adiposity, increase beta cell mass, and improve insulin sensitivity.

Topics: Animals; Body Composition; Body Weight; Female; Follistatin-Related Proteins; Glucose; Homeostasis; Humans; Hypertension; Islets of Langerhans; Ligands; Liver; Mice; Mice, Knockout; Transforming Growth Factor beta

Angiotensin II blockade and spironolactone effectively reduces proteinuria in humans. To clarify the mechanisms of the beneficial effect of blockade of both aldosterone and angiotensin II, we associated the aldosterone antagonist eplerenone to an angiotensin-converting enzyme inhibitor (ACEI) and examined the effect on renal transforming growth factor (TGF)-beta expression and oxidative stress by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the Dahl salt-sensitive rat with heart failure (DSHF).. Dahl salt-resistant control rats and DSHF rats were fed with 8% NaCl diet and at 11 weeks the DSHF rats were treated with vehicle, eplerenone (Epl), trandolapril or a combination of both drugs for 7 weeks.. DSHF rats showed increased NADPH oxidase and decreased superoxide dismutase (SOD) resulting in increased oxidative stress. ACEI and Epl reduced NADPH oxidase showing an additive effect in their combination; ACEI increased manganese SOD (MnSOD) and Epl increased MnSOD, copper-zinc SOD and catalase, resulting in the lowest levels of oxidative stress with the combination therapy. Glomerulosclerosis and proteinuria were increased in the DSHF rats, and Epl suppressed them more effectively than ACEI to levels not different from the combination of both, showing a positive correlation with NADPH oxidase expression and TGF-beta. Renal TGF-beta was specifically suppressed with Epl. The association of Epl to ACEI is beneficial due to further reduction of NADPH oxidase and specific inhibition of TGF-beta resulting in improvement of renal damage.

Topics: Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiac Output, Low; Drug Synergism; Eplerenone; Hypertension; Indoles; Kidney; Male; Mineralocorticoid Receptor Antagonists; NADPH Oxidases; Oxidative Stress; Rats; Rats, Inbred Dahl; Reactive Oxygen Species; Sodium-Potassium-Exchanging ATPase; Spironolactone; Superoxide Dismutase; Transforming Growth Factor beta

The metabolic syndrome (MS) is associated with left ventricular hypertrophy (LVH). Previous evidence has shown that LVH is favoured by low levels of atrial natriuretic peptide (ANP), independently from blood pressure (BP), in hypertension. Although levels of natriuretic peptides are known to be lower in obesity, plasma ANP levels have not yet been assessed in MS. We aimed to assess the ANP levels and their relationship with left ventricular mass (LVM) in patients affected by MS.. One hundred and twenty-eight essential hypertensive patients were included in the study: 51 with MS and 77 without MS. Clinical, echocardiographical and biochemical parameters, and levels of both N-terminal (NT)-proANP and alphaANP were assessed.. Hypertensive patients affected by MS had higher LVM and increased frequency of LVH. NT-proANP levels were significantly lower in MS, independent of waist circumference (WC). Log(NT-proANP) levels were significantly inversely related to left ventricular mass index (LVMI) (beta = -0.360, P < 0.001) and LVM/height (beta = -0.370, P < 0.001) in the whole hypertensive population by multiple linear regression analysis. The relationship of log(NT-proANP) with LVM was more enhanced in patients with MS.. The present study demonstrates that levels of NT-proANP are significantly reduced in hypertensive patients affected by MS, and they are significantly inversely related to the increased LVM observed in these patients. Our findings, while supporting previous experimental and clinical evidence of the antihypertrophic role of ANP in hypertension, may help to identify one of the possible mechanisms directly underlying LVH in MS.

Topics: Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Case-Control Studies; Echocardiography, Doppler; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Linear Models; Male; Metabolic Syndrome; Middle Aged; Predictive Value of Tests; Protein Precursors; Rome; Stroke Volume; Transforming Growth Factor beta

Previous studies have shown that metabolic syndrome (MS) is associated with an increased susceptibility to develop cardiovascular damage (CD). Experimental evidence indicates that inflammation and fibrosis could play a critical role in the development of CD in hypertension. This issue has not been clarified yet in patients with MS. The aim of our study was to investigate the relationship between markers of inflammation and fibrosis with CD in hypertensive patients with and without MS.. One hundred twenty-eight essential hypertensive patients were included in the study: 51 with MS and 77 without MS. Clinical, biochemical parameters, 24-h urinary albumin excretion rate (UAER), levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), and procollagen type 1 carboxy-terminal propeptide (PICP) were measured. All patients underwent an echocardiographic examination with transmitral Doppler and tissue Doppler imaging (TDI).. Left ventricular mass indexed by height(2.7) (LVM/h(2.7)) (P < .001), early diastolic peak flow velocity/early myocardial diastolic velocity ratio (E/Em ratio), a TDI index of diastolic function (P < .001), and 24-h UAER (P < .05) were significantly higher in the group with MS, whereas peak myocardial systolic velocity (Sm), a TDI index of systolic function (P < .001), was lower. Serum levels of CRP (P < .001), TNF-alpha (P < .05), TGF-beta (P < .01), and PICP (P < .001) were significantly increased in MS. These markers were significantly related to higher LVMI(2.7), higher E/Em ratio, and increased 24-h UAER and a lower Sm in the whole population, with a further significant enhancement in MS.. Cardiovascular damage is more frequent in hypertensives with MS than in hypertensives without MS, and this is significantly related to the increased levels of inflammation and fibrosis found in hypertensives with MS.

Topics: Albuminuria; Biomarkers; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Case-Control Studies; Diastole; Female; Fibrosis; Humans; Hypertension; Hypertrophy, Left Ventricular; Inflammation; Male; Metabolic Syndrome; Middle Aged; Peptide Fragments; Procollagen; Systole; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Extracellular matrix expansion in the glomerular mesangium contributes to the development of glomerulosclerosis and chronic renal disease in arterial hypertension. Transforming growth factor-beta1 (TGF-beta1), matrix metalloproteinases (MMPs), and tissue inhibitors of MMPs (TIMPs) are involved in this process. Conflicting data are reported on the effects of angiotensin II (Ang II) and the response to angiotensin-converting enzyme inhibition on MMPs and TIMPs in early stages of hypertensive glomerular damage. We therefore investigated the effects of Ang II-dependent hypertension on MMP-2, MMP-9, TIMP-1, and TIMP-2 in isolated glomeruli of 8-week-old homozygous male rats overexpressing the mouse Ren2 gene [TGR(mRen2)27]. At this age, systolic blood pressure was already significantly elevated in Ren2 compared with Sprague-Dawley (SD) rats (197 +/- 38 versus 125 +/- 16 mm Hg, p < 0.01). Ren2 exhibited renal damage as determined by increased urinary albumin excretion, focal glomerulosclerosis, mesangial matrix expansion, and alpha-smooth muscle actin deposition. Quantification of mRNA levels in isolated glomeruli by real-time polymerase chain reaction showed a significant increase of TGF-beta1, a 2.3- and a 2.6-fold increase of MMP-2 and TIMP-1 in Ren2 compared with SD (p < 0.01, respectively) and no strain differences for TIMP-2. In contrast, MMP-9 mRNA expression was markedly suppressed to 10% of control levels in Ren2 (p < 0.01). Early treatment with ramipril completely prevented renal damage in Ren2 and restored mRNA expression of TGF-beta1, MMP-2, and TIMP-1 to SD control levels. Interestingly, down-regulation of MMP-9 mRNA, protein, and activity was not affected by ramipril, indicating that the protective effect of this compound is not attributable to restoration of MMP-9 in the glomerulus.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Blood Pressure; Blotting, Western; Body Weight; Gelatin; Gene Expression Regulation, Enzymologic; Glomerular Mesangium; Hypertension; Immunohistochemistry; Kidney Diseases; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Serine Endopeptidases; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta; Transforming Growth Factor beta1

GLUT1 upregulation and increased glucose transport activity may contribute to extracellullar matrix (ECM) accumulation characterizing diabetic nephropathy (DN). Rats of the Milan hypertensive strain (MHS) are resistant to both hypertensive and diabetic renal disease, due to a haemodynamic protection. On the contrary, those of the Milan normotensive strain (MNS) develop spontaneous glomerulosclerosis, and when rendered diabetic, show typical morphological and haemodynamic changes.. To assess whether susceptibility to diabetic glomerulopathy in MNS rats is associated with higher glucose transporter 1 (GLUT1) expression (and glucose transport activity) vs MHS rats, diabetic and nondiabetic MNS and MHS rats were followed for 6 months and mesangial cells derived from these animals were exposed to high glucose (HG) vs normal glucose (NG) conditions.. Glomerular expression of GLUT1 protein and ECM and transforming growth factor-beta (TGF-beta) mRNA was significantly upregulated in diabetic vs nondiabetic MNS, but not MHS rats. Upon exposure to HG and/or TGF-beta, mesangial cells from 1- and 8-month-old MNS rats showed higher glucose transport activity and GLUT1 membrane expression than those from age-matched MHS rats. Likewise, ECM and TGF-beta production increased more markedly in response to HG and/or TGF-beta in MNS vs MHS mesangial cells.. These data indicate that susceptibility to diabetic glomerulopathy in MNS rats is associated with increased GLUT1-dependent glucose transport activity in response to hyperglycaemia and/or TGF-beta, which may amplify ECM overproduction. Conversely, the haemodynamic protection from glomerulosclerosis in MHS rats is associated with lack of upregulation of TGF-beta/GLUT1 axis, thus supporting the concept that this axis may represent the link between haemodynamic and metabolic mechanisms of injury.

Topics: Animals; Diabetes Complications; Diabetes Mellitus, Experimental; Disease Susceptibility; Extracellular Matrix; Glomerulonephritis; Glucose; Glucose Transporter Type 1; Hyperglycemia; Hypertension; Immunity, Innate; Rats; Rats, Mutant Strains; Transforming Growth Factor beta; Up-Regulation

An angiotensin-converting enzyme inhibitor (ACE-I) reduces cardiac remodeling and a bradykinin B2 receptor (B2R) antagonist partially abolishes this ACE-I effect. However, bradykinin has two different types of receptor, the B1 receptor (B1R) and B2R. Although B1R is induced under several pathological conditions, including hypertension, the role of cardiac B1R in hypertension is not clear. We therefore investigated the role of cardiac B1R in stroke-prone spontaneously hypertensive rats (SHR-SP) and Wistar-Kyoto (WKY) rats. The B1R mRNA expression level in the heart was significantly higher in SHR-SP than in WKY rats. Chronic infusion of a B1R antagonist for 4 weeks significantly elevated blood pressure and left-ventricular weight of SHR-SP. Morphological analysis indicated that cardiomyocyte size and cardiac fibrosis significantly increased after administration of the B1R antagonist. The phosphorylation of mitogen-activated protein (MAP) kinases, including ERK, p38, and JNK, was significantly increased in the hearts of SHR-SP rats receiving the B1R antagonist. The TGF-beta1 expression level was significantly increased in SHR-SP rats treated with the B1R antagonist compared to that in WKY rats. The B1R antagonist significantly increased phosphorylation of Thr495 in endothelial nitric oxide synthase (eNOS), which is an inhibitory site of eNOS. These results suggest that the role of B1R in the heart may be attenuation of cardiac remodeling via inhibition of the expression of MAP kinases and TGF-beta1 through an increase in eNOS activity in a hypertensive condition.

Topics: Animals; Antihypertensive Agents; Bradykinin B1 Receptor Antagonists; Disease Models, Animal; Enzyme Activation; Gene Expression Profiling; Gene Expression Regulation; Heart; Hypertension; Male; Mitogen-Activated Protein Kinases; Nitric Oxide Synthase Type III; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Bradykinin B1; RNA, Messenger; Stroke; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Remodeling

Hypertension is a complex disease influenced by multiple genetic and environmental factors. The TGF-beta signaling pathway has a long recognized role in blood pressure homeostasis. In this issue of Cell, Zacchigna et al. (2006) report that the secreted protein Emilin1 is a negative regulator of TGF-beta signaling. Emilin1 knockout mice display elevated blood pressure due to increased TGF-beta signaling in the vasculature.

Topics: Animals; Blood Pressure; Blood Vessels; Homeostasis; Humans; Hypertension; Membrane Glycoproteins; Mice; Mice, Knockout; Signal Transduction; Transforming Growth Factor beta

TGF-beta proteins are main regulators of blood vessel development and maintenance. Here, we report an unprecedented link between TGF-beta signaling and arterial hypertension based on the analysis of mice mutant for Emilin1, a cysteine-rich secreted glycoprotein expressed in the vascular tree. Emilin1 knockout animals display increased blood pressure, increased peripheral vascular resistance, and reduced vessel size. Mechanistically, we found that Emilin1 inhibits TGF-beta signaling by binding specifically to the proTGF-beta precursor and preventing its maturation by furin convertases in the extracellular space. In support of these findings, genetic inactivation of Emilin1 causes increased TGF-beta signaling in the vascular wall. Strikingly, high blood pressure observed in Emilin1 mutants is rescued to normal levels upon inactivation of a single TGF-beta1 allele. This study highlights the importance of modulation of TGF-beta availability in the pathogenesis of hypertension.

Topics: Animals; Arteries; Blood Pressure; Furin; Gene Dosage; Genes, Reporter; Homeostasis; Humans; Hypertension; Membrane Glycoproteins; Mice; Mice, Knockout; Mice, Transgenic; Nodal Protein; Phenotype; Protein Precursors; Protein Structure, Tertiary; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta; Xenopus laevis

Gómez-Garre et al. report increased expression of connective tissue growth factor and transforming growth factor-beta and worsening of remodeling in subcutaneous arterioles of patients with essential hypertension during amlodipine treatment. Losartan improves remodeling without changes in cytokine expression. The discordant effects of two well-accepted treatments for hypertension underline the need for further studies on therapy-induced changes in arteriolar remodeling.

Topics: Amlodipine; Antihypertensive Agents; Arterioles; Connective Tissue Growth Factor; Humans; Hypertension; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Losartan; Transforming Growth Factor beta

We investigated the contribution of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) generation to the pathogenesis of diastolic heart failure (DHF) in Dahl salt-sensitive (DS) hypertensive rats, with the aim of testing our hypothesis that the cardioprotective effects of angiotensin II (Ang II) blockade are provided by the suppression of this pathway.. DS rats were maintained on high (H: 8.0% NaCl) or low (L: 0.3% NaCl) salt diets from age 7 to 17 weeks. DS/H rats were also treated with candesartan cilexetil (10 mg/kg per day, orally) or a superoxide dismutase mimetic, tempol (3 mmol/l in drinking water) from age 7 to 17 weeks.. DS/H rats represented hypertension, left ventricular (LV) relaxation abnormality and myocardial stiffening with preserved systolic heart function. As compared with DS/L rats, DS/H rats showed higher levels of transforming growth factor-beta (TGF-beta), connective tissue growth factor (CTGF), p22phox and gp91phox mRNA expression, NADPH oxidase activity and thiobarbituric acid-reactive substance (TBARS) contents in LV tissues. Gene expression of uncoupling protein-2 (UCP-2), an inner mitochondrial membrane proton transporter, was also 2.8 +/- 0.5-fold higher. In DS/H rats, treatment with candesartan did not alter blood pressure, but resulted in a marked improvement of the hemodynamic deterioration; these therapeutic effects were accompanied by decreases in myocardial NADPH oxidase activity, TBARS contents and the expression of TGF-beta, CTGF, p22phox, gp91phox and UCP-2. Similar therapeutic effects were provided by treatment with tempol in DS/H rats.. Our data suggest that NADPH oxidase-mediated ROS production contributes to the pathogenesis of DHF in DS hypertensive rats, and that the cardioprotective effects of AngII blockade are, at least partially, mediated through the suppression of this pathway.

Topics: Angiotensin II; Animals; Blood Pressure; Collagen; Connective Tissue Growth Factor; Diastole; Gene Expression; Heart Failure; Heart Ventricles; Hypertension; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Ion Channels; Lung; Male; Membrane Transport Proteins; Mitochondrial Proteins; Myocardium; NADPH Oxidases; Natriuretic Peptide, Brain; Organ Size; Rats; Rats, Inbred Dahl; Reactive Oxygen Species; Thiobarbituric Acid Reactive Substances; Transforming Growth Factor beta; Uncoupling Protein 2; Ventricular Dysfunction, Left

Recent studies have suggested that aldosterone plays a role in the pathogenesis of renal injury. In this study, we investigated whether local angiotensin II (Ang II) activity contributes to the progression of renal injury in aldosterone/salt-induced hypertensive rats. Uninephrectomized rats were treated with 1% NaCl in a drinking solution and one of the following combinations for 6 weeks: vehicle (2% ethanol, s.c.; n=9), aldosterone (0.75 mug/h, s.c.; n=8), aldosterone+Ang II type 1 receptor blocker olmesartan (10 mg/kg/day, p.o.; n=8), or aldosterone+olmesartan (100 mg/kg/day, p.o.; n=9). Aldosterone/salt-treated hypertensive rats exhibited severe proteinuria and renal injury characterized by glomerular sclerosis and tubulointerstitial fibrosis. Aldosterone/salt-induced renal injury was associated with augmented expression of angiotensin converting enzyme and Ang II levels in the renal cortex and medullary tissues. Renal cortical and medullary mRNA expression of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) as well as the collagen contents were increased in aldosterone/salt-treated hypertensive rats. Treatment with olmesartan (10 or 100 mg/kg/day) had no effect on blood pressure but attenuated proteinuria in a dose-dependent manner. Olmesartan at 10 mg/kg/day tended to decrease renal cortical and medullary Ang II levels, TGF-beta and CTGF expression, and collagen contents; however, these changes were not significant. On the other hand, an ultrahigh dose of olmesartan (100 mg/kg/day) significantly decreased these values and ameliorated renal injury. These data suggest that augmented local Ang II activity contributes, at least partially, to the progression of aldosterone/salt-dependent renal injury.

Topics: Aldosterone; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Pressure; Body Weight; Collagen; Connective Tissue Growth Factor; Creatine; Hypertension; Imidazoles; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Kidney; Male; Nephrectomy; Organ Size; Peptidyl-Dipeptidase A; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Sodium Chloride; Tetrazoles; Transforming Growth Factor beta

Aldosterone promotes cardiovascular inflammation and remodeling, both of which are characteristic changes in hypertensive and failing hearts. Since chronic inhibition of nitric oxide (NO) synthase with N(omega)-nitro-L-arginine methyl ester (L-NAME) induces systemic hypertension associated with cardiovascular inflammation and remodeling, we examined the potential role of aldosterone in this process using eplerenone, a selective aldosterone receptor antagonist. Ten-week-old male Wistar-Kyoto rats were randomly divided into 3 groups: the control group (no treatment), the L-NAME group (received L-NAME 1 g/L in drinking water), and the L-NAME+Eplerenone group (L-NAME plus eplerenone at 100 mg/kg/day). After 8 weeks of the treatment, the L-NAME group showed significantly higher systolic blood pressure than the control group (198 +/- 7 vs. 141 +/- 3 mmHg, P < 0.05). Eplerenone did not affect the increase in blood pressure caused by L-NAME (189 +/- 12 mmHg). Chronic inhibition of NO synthesis increased the plasma aldosterone concentration and CYP11B2 mRNA in adrenal glands. Cardiac inflammation and fibrosis were detected in the L-NAME group, while both changes were completely prevented by eplerenone. Cardiac hypertrophy was induced in L-NAME group, but was partially prevented by eplerenone. In the L-NAME group, left ventricular fractional shortening (LVFS: 27 +/- 2 vs. 38 +/- 1%) and E/A ratio (1.7 +/- 0.1 vs. 2.1 +/- 0.1) were significantly lower and LV end-diastolic pressure (LVEDP) was higher (4.9 +/- 0.6 vs. 13.9 +/- 0.5 mmHg) without LV enlargement, compared with those in the control group (P < 0.05). Eplerenone completely normalized LVFS (36 +/- 2%), E/A ratio (2.2 +/- 0.1), and LVEDP (6.2 +/- 0.7 mmHg). These results suggest that chronic inhibition of NO synthesis induces cardiac inflammation and dysfunction via an aldosterone receptor-dependent mechanism.

Topics: Actins; Aldosterone; Animals; Blotting, Western; Cytochrome P-450 CYP11B2; Drug Therapy, Combination; Eplerenone; Fibrosis; Heart Failure; Heart Ventricles; Hypertension; Immunohistochemistry; Male; Mineralocorticoid Receptor Antagonists; NF-kappa B; NG-Nitroarginine Methyl Ester; Nitric Oxide; Peptide Fragments; Proliferating Cell Nuclear Antigen; Protein Precursors; Random Allocation; Rats; Rats, Inbred WKY; Receptors, Mineralocorticoid; RNA, Messenger; Spironolactone; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Animals; Arteries; Blood Pressure; Humans; Hypertension; Membrane Glycoproteins; Mice; Mice, Knockout; Signal Transduction; Transforming Growth Factor beta; Xenopus laevis

The study revealed an increase in the serum levels of TGF-beta1 and the N-terminal peptide procollagen type III in patients with essential arterial hypertension (EAH), as well as an association between this increase and the duration of the disease, mean day arterial pressure profile, and left ventricular hypertrophy. An increased leukocyte functional activity is associated with disturbances in left ventricular diastolic function and an increase in TGF-beta1 serum concentration in EAH. The authors conclude that leukocytes participate in the development of myocardial hypertrophy and cardial fibrosis through the secretion of pro-inflammatory cytokines and peptide growth factors within the process of their activation.

Topics: Adult; Biomarkers; Blood Pressure; Disease Progression; Female; Fibrosis; Follow-Up Studies; Humans; Hypertension; Hypertrophy, Left Ventricular; Leukocytes; Male; Middle Aged; Myocardium; Peptide Fragments; Procollagen; Transforming Growth Factor beta; Transforming Growth Factor beta1

The present study was carried out to investigate the role of hypertension in the genesis and localization of intimal lesions and medial remodelling found in the prestenotic segment in relation to a severe stenosis of the abdominal aorta just below the diaphragm. Male young rats were divided randomly into operated group, animals submitted to surgical abdominal aorta stenosis, and sham-operated group, a control group of animals submitted to sham operation to simulate abdominal aorta stenosis. Aortas in the hypertensive prestenotic segment with increased circumferential wall tension associated with normal tensile stress, laminar flow/normal wall shear stress were characterized by enlarged heterogeneous endothelial cells elongated in the direction of the blood flow, diffusely distributed conspicuous neointimal plaques and medial thickening. The immunohistochemical analysis revealed an increased expression of eNOS, iNOS, nitrotyrosine and transforming growth factor-beta (TGF-beta) in endothelial cells and/or smooth muscle cells in this segment. Our findings suggest that increased circumferential wall tension due to hypertension plays a pivotal role in the remodelling of the prestenotic segment through biomechanical effects on oxidative stress and increased TGF-beta expression. Further studies are needed to clarify the intrinsic pathogenetic mechanism of focal distribution of the neointimal plaques in the hypertensive segment.

Topics: Animals; Aorta, Abdominal; Aortic Valve Stenosis; Biomarkers; Hypertension; Immunohistochemistry; Male; Microscopy, Electron, Transmission; Models, Animal; Models, Cardiovascular; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Pulsatile Flow; Rats; Rats, Wistar; Stress, Mechanical; Transforming Growth Factor beta; Tunica Intima; Tyrosine; Ultrasonography, Doppler, Color

Rho-kinase plays a crucial role in various cellular functions. To elucidate molecular mechanisms of Rho-kinase-mediated cardiovascular remodeling in vivo, we evaluated whether a signaling pathway through Rho is involved, and whether Y-27632, a specific Rho-kinase inhibitor, stimulates endothelial nitric oxide synthase (eNOS) and suppresses the oxidative stress and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) pathway in the left ventricle of Dahl salt-sensitive hypertensive (DS) rats.. Y-27632 (3 mg/kg per day) or vehicle were given for 5 weeks, from age 6 weeks to a stage of left ventricular hypertrophy (11 weeks). Age-matched Dahl salt-resistant (DR) rats fed the same diet served as a control group.. Increased left ventricular weight in the hypertrophy stage was significantly ameliorated by Y-27632. Upregulated RhoA protein, Rho-kinase gene expression and myosin light-chain phosphorylation in the hypertrophy stage were suppressed by Y-27632. Increased expression of NAD(P)H oxidase p22phox, p47phox, gp91phox and LOX-1 in DS rats were inhibited by Y-27632. Upregulated protein kinase Cepsilon and p65 nuclear factor-kappaB phosphorylation in DS rats was reduced by Y-27632. In contrast, downregulated eNOS expression in hypertrophy stage was upregulated by Y-27632. Y-27632 effectively inhibited vascular lesion formation, such as medial thickness and perivascular fibrosis, and suppressed transforming growth factor-beta1, type I and III collagen, and fibronectin gene expression.. Inhibiting the Rho-kinase pathway may play a key role in the cardioprotective effect on cardiovascular remodeling associated with eNOS and the oxidative stress-LOX-1 pathway in DS rats, and may be at least a potential therapeutic strategy for hypertension with cardiac hypertrophy.

Topics: Amides; Animals; Collagen Type I; Collagen Type III; Coronary Vessels; Enzyme Inhibitors; Fibronectins; Hypertension; Intracellular Signaling Peptides and Proteins; Male; NADPH Oxidases; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Oxidative Stress; Phosphorylation; Protein Kinase C; Protein Kinase C-epsilon; Protein Serine-Threonine Kinases; Pyridines; Rats; Rats, Inbred Dahl; Receptors, LDL; Receptors, Oxidized LDL; rho-Associated Kinases; rhoA GTP-Binding Protein; RNA, Messenger; Scavenger Receptors, Class E; Signal Transduction; Transcription Factor RelA; Transforming Growth Factor beta; Transforming Growth Factor beta1

Brain abnormalities, preceded by a systemic inflammation, develop in spontaneously hypertensive stroke-prone rats (SHRSP). In this model, we investigated whether the hydrophilic statin, rosuvastatin, influences the development of inflammation associated with brain abnormalities. Because differences in hydrophilicity/hydrophobicity contribute to the differences in statin pharmacology, we also evaluated the effects of simvastatin, a lipophilic molecule. SHRSP, fed a high-salt diet, were treated long-term with vehicle or rosuvastatin (1 and 10 mg/kg per day). Brain abnormalities developed after 40+/-5 days and after 60+/-5 days of salt loading, in vehicle-treated and in rosuvastatin-treated (1 mg/kg per day) SHRSP, respectively. After 100 days of treatment, no damage was detectable in 30% of the rats treated with the highest dose of the drug. In comparison with vehicle-treated SHRSP, rosuvastatin treatment attenuated the transcription of monocyte chemoattractant protein-1, transforming growth factor-beta1, IL-1beta, and tumor necrosis factor-alpha in the kidney, and of P-selectin in brain vessels and increased the transcription of endothelial nitric oxide synthase mRNA in the aorta. Urinary excretion of acute-phase proteins increased with time in vehicle-treated animals but remained negligible in drug-treated animals. These effects are independent of changes in physiological parameters. Treatment of SHRSP with simvastatin (2 to 20 mg/kg per day) did not exert any protective effect.. Rosuvastatin attenuates inflammatory processes associated with cerebrovascular disease.

Topics: Acute-Phase Proteins; Animals; Cerebral Arteries; Chemokine CCL2; Fluorobenzenes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; P-Selectin; Proteinuria; Pyrimidines; Rats; Rats, Inbred SHR; RNA, Messenger; Rosuvastatin Calcium; Simvastatin; Sodium Chloride, Dietary; Stroke; Sulfonamides; Transcription, Genetic; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; Vasculitis

The extracellular matrix (ECM) determines the structural integrity of the heart and vasculature, participating in cardiovascular remodeling. We previously reported that adrenomedullin (AM) inhibited cellular proliferation and protein synthesis of cardiac fibroblasts; however, the precise mechanisms of AM actions as an antifibrotic factor remain unknown. The purpose of this study was to examine the biological actions of AM against the profibrotic factor angiotensin II (Ang II) in coronary adventitia.. Rats with hypertension induced by Ang II infusion were administered 0.06 mug/kg/min recombinant human AM subcutaneously for 14 days. The AM infusion significantly (p<0.05) reduced the Ang II-induced increase of coronary adventitial fibroblasts expressing Ki-67 and alpha-smooth muscle actin (alpha-SMA) in the left ventricle, by 65%, and 62%, respectively, without affecting systolic blood pressure, left ventricle/body weight, or cross-sectional area of myocardial fibers. Collagen deposition of coronary arteries was reduced by the AM infusion (-24%, p<0.01), and these effects of AM were accompanied by significant reductions in gene expression of type 1 collagen (-49%, p<0.05) and transforming growth factor-beta1 (TGF-beta1) (-55%, p<0.01). In cultured cardiac fibroblasts, 10(-7) mol/L AM exerted an inhibitory effect on TGF-beta1-induced alpha-SMA expression (p<0.01) that was mimicked by 8-bromo-cAMP and attenuated by the protein kinase A inhibitor H-89.. AM decreased Ang II-induced collagen deposition surrounding the coronary arteries, inhibiting myofibroblast differentiation and expressions of ECM-related genes in rats. The present findings further support the biological action of AM as an antifibrotic factor in vascular remodeling.

Topics: Actins; Adrenomedullin; Angiotensin II; Animals; Blood Pressure; Body Weight; Cardiotonic Agents; Cell Differentiation; Cell Division; Cell Size; Collagen Type I; Connective Tissue; Fibroblasts; Heart Ventricles; Humans; Hypertension; Male; Myocytes, Cardiac; Peptides; Rats; Rats, Wistar; Recombinant Proteins; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Remodeling

This study examined the role of transforming growth factor-beta (TGF-beta) in altering the glomerular permeability to albumin (P(alb)) during hypertension development in Dahl salt-sensitive (Dahl S) rats and whether TGF-beta acts by inhibiting the glomerular production of 20-HETE. The results indicate that the renal expression of TGF-beta doubles in Dahl S rats fed a high-salt diet for 7 days, and this is associated with a marked rise in P(alb) from 0.19+/-0.04 to 0.75+/-0.01 and changes in the ultrastructure of the glomerular filtration barrier. Chronic treatment of Dahl S rats with a TGF-beta neutralizing antibody prevented the increase in P(alb) and preserved the structure of glomerular capillaries. It had no effect on the rise in blood pressure produced by the high-salt diet. In other studies, preincubation of glomeruli isolated from Sprague Dawley rats with TGF-beta1 (10 ng/mL) for 15 minutes increased P(alb) from 0.01+/-0.01 to 0.60+/-0.02. This was associated with inhibition of the glomerular production of 20-HETE from 221+/-11 to 3.4+/-0.5 mug per 30 minutes per milligram of protein. Pretreatment of Sprague Dawley glomeruli with a stable analog of 20-HETE, 20-hydroxyeicosa-5(Z), 14(Z)-dienoic acid, reduced baseline P(alb) and opposed the effects of TGF-beta to increase P(alb). These studies indicate that upregulation of the glomerular formation of TGF-beta may contribute to the development of proteinuria and glomerular injury early in hypertension development in Dahl S rats by increasing P(alb) through inhibition of the glomerular production of 20-HETE.

Topics: Animals; Hydroxyeicosatetraenoic Acids; Hypertension; In Vitro Techniques; Kidney; Kidney Glomerulus; Microscopy, Electron; Permeability; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Serum Albumin, Bovine; Sodium Chloride, Dietary; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor (TGF)-beta1 has been shown to play a critical role in hypertensive nephropathy. We hypothesized that blocking TGF-beta1 signaling could attenuate renal fibrosis in a rat model of remnant kidney disease. Groups of six rats were subjected to 5/6 nephrectomy and received renal arterial injection of a doxycycline-regulated Smad7 gene or control empty vector using an ultrasound-microbubble-mediated system. Smad7 transgene expression within the kidney was tightly controlled by the addition of doxycycline in the daily drinking water. All animals were euthanized at week 4 for renal functional and histological examination. Hypertension of equivalent magnitude (190 to 200 mmHg) developed in both Smad7- and empty vector-treated rats. However, treatment with Smad7 substantially inhibited Smad2/3 activation and prevented progressive renal injury by inhibiting the rise of 24-hour proteinuria (P < 0.001) and serum creatinine (P < 0.001), preserving creatinine clearance (P < 0.05), and attenuating renal fibrosis and vascular sclerosis such as collagen I and III expression (P < 0.01) and myofibroblast accumulation (P < 0.001). In conclusion, TGF-beta/Smad signaling plays a critical role in renal fibrosis in a rat remnant kidney model. The ability of Smad7 to block Smad2/3 activation and attenuate renal and vascular sclerosis demonstrates that ultrasound-mediated Smad7 gene therapy may be a useful therapeutic strategy for the prevention of renal fibrosis in association with hypertension.

Topics: Animals; Blood Pressure; Blotting, Western; DNA-Binding Proteins; Doxycycline; Fibrosis; Gene Transfer Techniques; Genetic Vectors; Hypertension; Immunohistochemistry; Immunoprecipitation; Kidney; Male; Phosphorylation; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Smad7 Protein; Time Factors; Trans-Activators; Transforming Growth Factor beta; Transgenes; Ultrasonics

Rats of the Milan normotensive strain develop spontaneous glomerulosclerosis, whereas those of the Milan hypertensive strain are resistant to renal disease, possibly due to intrarenal artery hypertrophy protecting from systemic hypertension. To assess the role of hemodynamic versus metabolic factors in diabetic nephropathy, we investigated whether streptozotocin-induced diabetes accelerates glomerulosclerosis in Milan normotensive and/or removes (the hemodynamic) protection in Milan hypertensive rats by reducing preglomerular vascular resistance.. Diabetic and nondiabetic Milan normotensive, hypertensive, and progenitor Wistar rats were followed for 6 months for the assessment of renal function and structure.. Proteinuria increased in nondiabetic and diabetic normotensive and, to a lesser extent, in diabetic Wistar, but not hypertensive rats. Serum creatinine increased and creatinine clearance decreased in nondiabetic and diabetic normotensive rats at 6 months. At 1.5 months, diabetic normotensive, but not hypertensive rats showed increased glomerular filtration rate and filtration fraction, suggesting glomerular hypertension. Diabetic nephropathy was detected in diabetic normotensive and Wistar, but not hypertensive rats. Glomerular extracellular matrix and TGF-beta mRNA levels increased with diabetes (and age) in normotensive, but not hypertensive rats. Arterioles and interlobular arteries showed increased media thickness in hypertensive versus normotensive rats, with diabetes reducing it only in the normotensive.. These data show that Milan hypertensive rats are not susceptible to diabetic nephropathy, at variance with glomerulosclerosis-prone Milan normotensive rats, thus indicating the importance of genetic background. Our study suggests that the nature of this (genetic) protection might be hemodynamic, with intrarenal artery hypertrophy preventing diabetes-induced loss of autoregulation.

Topics: Animals; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Nephropathies; DNA Primers; Extracellular Matrix; Hemodynamics; Hypertension; Kidney; Proteinuria; Rats; Rats, Mutant Strains; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta

Diabetes and mesangial stretch caused by hypertension increase mesangial matrix deposition which is induced by local production of transforming growth factor beta 1 (TGF-beta1). Both conditions are associated with cortical GLUT1 overexpression. We evaluated the effect of genetically determined hypertension and its association with diabetes on urinary TGF-beta1 and cortical GLUT1 and GLUT2 expression.. We studied Wistar-Kyoto rats (controls, C) and spontaneously hypertensive rats (SHR), weighing approximately 210 g, 30 days after the injection of streptozotocin (diabetic, D) or citrate buffer (10 C, 9 SHR, 12 C-D and 15 SHR-D). Twenty-four-hour urine was collected for glucose, albumin, and TGF-beta1 determinations. Catheters were implanted into the femoral artery to measure the arterial blood pressure in conscious animals 1 day later. Then GLUT1 and GLUT2 protein levels (Western blotting) in renal cortex and medulla were evaluated.. The cortical GLUT1 levels were 5, 2, and 7 times higher in SHR, C-D, and SHR-D groups versus C group (p < 0.05); the GLUT2 contents were 1.5, 1.8, and 2.3 times higher in SHR, C-D and SHR-D groups versus C group (p < 0.05). The urinary TGF-beta1 level was elevated by diabetes and diabetes and hypertension, but not by hypertension alone: 1.39 +/- 0.2, 2.34 +/- 0.6, 18.2 +/- 3.2, and 28.8 +/- 7.6 ng/24 h, respectively, in C, SHR, C-D, and SHR-D groups (p < 0.05).. Diabetes, hypertension, and especially their association increase the renal cortical GLUT1 and GLUT2 levels. The magnitude of GLUT1 overexpression caused by hypertension is higher than that induced by diabetes alone. The impact on urinary TGF-beta1 occurs when diabetes and hypertension are associated, suggesting an effect that is triggered in the presence of GLUT1 overexpression and hyperglycemia.

Topics: Animals; Diabetes Mellitus, Experimental; Glucose Transporter Type 1; Glucose Transporter Type 2; Hypertension; Kidney Cortex; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Streptozocin; Transforming Growth Factor beta; Transforming Growth Factor beta1

Dahl salt-sensitive (DS) rats given a high-salt diet develop renal lesions that are virtually identical to those in human hypertensive nephrosclerosis and are associated with increased oxidative stress. This study looks at the effects of a superoxide scavenger in preventing of hypertensive renal damage in high-salt-treated DS rats.. The DS rats (n = 5 per group) were treated with 0.3% NaCl diets (LS), 8% NaCl diets (HS), and 8% NaCl diets plus 10 mmol/L tempol in drinking water (HS+T) for 5 weeks. Systolic blood pressure (SBP) was measured by the tail-cuff method. As markers of renal damage, we measured serum creatinine, creatinine clearance, histopathologic indices, and transforming growth factor-beta1 (TGF-beta1; a mediator for renal fibrosis) expression. In addition, 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells and expression of heme oxygenase-1 (HO-1) were quantified as markers of oxidative stress.. We found that a high-salt diet (8% NaCl) led to the development of hypertension, increased oxidative stress in the renal tissue (8-OHdG immunoreactive staining and HO-1 protein expression), increased renal histopathologic damage (arteriosclerosis index, matrix score, and interstitial volume) accompanied by accumulation of TGF-beta1, and decreased creatinine clearance in the DS rats. These adverse effects of salt were prevented by the tempol supplementation.. Histopathologic and biochemical findings indicate that, in the DS rat, salt-induced hypertensive nephropathy is associated with increased oxidative stress. Superoxide mimetic tempol can reduce this detrimental effect of salt feeding through TGF-beta1 suppression and consequently prevent the development of hypertension and hypertensive nephropathy.

Topics: Animals; Heat-Shock Proteins; Heme Oxygenase (Decyclizing); Hypertension; Immunohistochemistry; Kidney; Male; Oxidative Stress; Oxygenases; Rats; Rats, Inbred Dahl; Sodium Chloride; Superoxides; Systole; Transforming Growth Factor beta

To investigate the effects and mechanisms of Shexiang Baoxin Pill (SBP) on myocardial fibrosis in spontaneous hypertensive rats (SHR).. SHR of 12 weeks old were divided into the SBP group, the control group (treated with benazepril) and the model control group. The effects on such indexes as systolic blood pressure (SBP), left ventricular mass (LVM), left ventricular mass index (LVMI), content of myocardial collagen (MC) in left ventricle, extracellular matrix fibronectin (FN), laminin (LN), cardiac fibroblast (cFb) and transforming growth factor-beta1 (TGF-beta1) were determined after 12 weeks of treatment.. SBP had no marked pressure depressive effect, but had the effect similar to that of benazepril in reducing the level of LVM, LVMI and content of MC (P < 0.05), as well as the content of LN, FN in myocardium, cFb count and TGF-beta1 expression (P < 0.05).. SBP can prevent and treat myocardial fibrosis, whose action is independent of its hypotensive effect. The mechanism may be associated with such factors as the decrease of MC synthesis in left ventricle and the deposition of extracellular matrix.

Topics: Animals; Collagen; Drugs, Chinese Herbal; Fibrosis; Hypertension; Hypertrophy, Left Ventricular; Male; Myocardium; Phytotherapy; Random Allocation; Rats; Rats, Inbred SHR; Transforming Growth Factor beta; Transforming Growth Factor beta1

ACE inhibitors are widely used to antagonize the biological activity of angiotensin II in hypertensive heart disease. Oestrogen reduces angiotensin type 1 receptor expression, and thereby modifies angiotensin signalling.. To investigate the interaction of oestrogen status and ACE inhibition on the development of left ventricular hypertrophy and expression of transforming growth factor (TGF)-beta(1) in female spontaneously hypertensive rats (SHR).. Intact female SHR, ovariectomised SHR, and ovariectomised SHR with 17beta-oestradiol (E2) replacement therapy were either treated with placebo or the ACE inhibitor moexiprilat. Blood pressure, left ventricular hypertrophy, and expression of TGF-beta(1) and TGF-beta(1)-regulated genes were investigated. ACE inhibition reduced blood pressure in all groups. When normalised to blood pressure, a significant reduction in hypertrophy was found in ovariectomised animals receiving E2. Expression of TGF-beta(1) was increased in all three groups treated with the ACE inhibitor, with top levels in ovariectomised animals. Moreover, expression of ornithine decarboxylase (ODC), an adrenoceptor dependent gene, downstream of TGF-beta(1), was up-regulated upon ACE inhibition, except in animals which were ovariectomised and oestrogen supplemented. Parathyroid hormone-related peptide, a growth factor negatively regulated by TGF-beta(1), was down-regulated in all animals receiving the ACE inhibitor.. ACE inhibition modulated TGF-beta(1) and TGF-beta(1) dependent genes. Oestrogen deficiency alone did not influence the progression of cardiac hypertrophy in this model of female SHR.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Disease Progression; Estradiol; Estrogens; Female; Hypertension; Hypertrophy, Left Ventricular; Myocardium; Ovariectomy; Rats; Rats, Inbred SHR; Tetrahydroisoquinolines; Transforming Growth Factor beta; Transforming Growth Factor beta1

This study has been designed to evaluate the relationship among transforming growth factor beta1 (TGFbeta1) and some measurements of diastolic function in a population of hypertensive subjects with normal left ventricular ejection fraction. We studied 67 hypertensive outpatients who according to their BMI levels were subdivided into three groups: lean (L), overweight (OW) and obese (OB) hypertensives (HT). Circulating TGFbeta1 and M- and B-mode echocardiography was determined. All hypertensives were further subgrouped, according to European Society of Cardiology Guidelines, into two subsets of patients with normal diastolic function or with diastolic dysfunction. Prevalence of left ventricular hypertrophy (LVH) was determined in all the groups. TGFbeta1, left ventricular mass (LVM), LVM/h(2.7), E-wave deceleration time and isovolumic relaxation time (IVRT) were significantly (P < 0.005) higher and E/A velocity ratio was significantly (P < 0.05) lower in OW-HT and OB-HT than in L-HT. Prevalence of LVH was significantly higher (P < 0.03) in group OB-HT than in L-HT. TGFbeta1 (P < 0.004), LVM/h(2.7) (P < 0.001) and prevalence of LVH were (P < 0.01) significantly higher in hypertensives with diastolic dysfunction than hypertensives with normal diastolic function. TGFbeta1 levels were positively correlated with BMI (r = 0.60; P < 0.0001), LVM/h(2.7) (r = 0.28; P < 0.03), IVRT (r = 0.30; P < 0.02) and negatively with E/A ratio (r = -0.38; P < 0.002) in all HT. Multiple regression analysis indicated that TGFbeta1, BMI and IVRT were independently related to E/A ratio explaining 71% of its variability (r = 0.84; P < 0.0001). This relationship was independent of LVH, age and HR suggesting that TGFbeta1 overproduction may be considered a pathophysiological mechanism in the development of left ventricular filling abnormalities in obesity-associated hypertension.

Topics: Adult; Aged; Biomarkers; Diastole; Echocardiography; Enzyme-Linked Immunosorbent Assay; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Middle Aged; Myocardial Contraction; Obesity; Regression Analysis; Risk Factors; Stroke Volume; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Dysfunction, Left

We examined the age-related changes in cardiac expression of angiogenic molecules during the development of cardiac remodeling in stroke-prone spontaneously hypertensive rats (SHRSP) in comparison with those in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Vascular endothelial growth factor (VEGF) was highly upregulated in SHRSP aged 20 weeks compared with the same age of WKY, but it was downregulated at 40 weeks. On the other hand, KDR, an angiogenic receptor of VEGF, and endothelial nitric oxide synthase, which is important in the VEGF-mediated angiogenic pathway, were markedly downregulated in SHRSP from 20 weeks of age. Such age-related changes in their expression levels seen in SHRSP were quite different from those in SHR. In both SHR and SHRSP, transforming growth factor-beta1 (TGF-beta1) expression was increased with age, although SHRSP showed more marked upregulation. Cardiac remodeling in SHRSP was characterized by decreased coronary capillary density, cardiomyocyte hypertrophy, and cardiac fibrosis. We conclude that, in addition to overexpression of TGF-beta1, which appears to play a pivotal role in promoting cardiac hypertrophy and fibrosis, a defect of the VEGF-KDR system could result in impaired physiologic coronary angiogenesis in SHRSP, contributing to cardiac deteroration associated with myocardial ischemia in this malignant hypertensive model.

Topics: Age Factors; Animals; Capillaries; Cardiomegaly; Coronary Vessels; Down-Regulation; Fibrosis; Gene Expression; Heart Ventricles; Hypertension; Myocardium; Neovascularization, Physiologic; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rats; Rats, Inbred SHR; Rats, Wistar; Stroke; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

The effects of iptakalim, a new ATP-sensitive potassium channel opener, were studied in spontaneously hypertensive rats (SHR). Treatment of 12-week-old male SHR (six animals in each group) with iptakalim by gastric lavage at doses of 1, 3, or 9 mg/kg/day for 12 weeks resulted in a lowering of blood pressure. Iptakalim provided significant renoprotection to SHR rats as measured by decreased proteinuria and improved renal function. Histological evidence demonstrated that iptakalim could reverse renal vascular remodeling (of afferent arterioles, arcuate arteries, or interlobular arteries), and improve pathological changes of glomerular, renal interstitial, and glomerular filtration membranes. These effects were accompanied by the decreased circulation and intrarenal concentrations of endothelin 1 and transforming growth factor beta1 (TGF-beta1), and down-regulated overexpression of genes for ET-1, endothelin-converting enzyme 1, TGF-beta1, and the subunits of ATP-sensitive potassium channels (K(ATP)), Kir1.1 and Kir6.1, in the kidney during hypertension. Abnormal expression of matrix components [collagen IV, fibronectin, matrix metalloproteinase 9 (MMP-9) and MMP tissue inhibitor 1 (TIMP-1)] was also significantly reversed by iptakalim. Our results demonstrate that chronic treatment with iptakalim not only reduces blood pressure but also preserves renal structure and function in SHR. In addition to reducing blood pressure, the renoprotective of iptakalim may be involved in inhibiting the circulation and intrarenal concentrations of endothelin 1 and TGF-beta1, regulating the expression of K(ATP) genes and correcting MMP-9/TIMP-1 imbalance in renal tissue, which may result in reducing the accumulation of extracellular matrix molecules.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; ATP-Binding Cassette Transporters; Benzazepines; Endothelin-1; Extracellular Matrix; Hemodynamics; Hypertension; Immunohistochemistry; KATP Channels; Kidney; Kidney Diseases; Kidney Function Tests; Potassium Channels, Inwardly Rectifying; Propylamines; Rats; Rats, Inbred SHR; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Diabetes Mellitus; Fibrosis; Humans; Hypertension; Obesity; Risk Factors; Schistosomiasis; Smoking; Somatostatin; Transforming Growth Factor beta; Transforming Growth Factor beta1

We investigate the role of transforming growth factor-beta (TGF-beta) in hypertension and renal failure progression in uremic rats, and whether it modulates the endothelin (ET) system.. Following renal mass reduction, uremic rats (Nx) received the pan-specific TGF-beta neutralizing antibody 1D11 (0.5 mg/kg, three times/week), the isotype control antibody 13C4 or the AT1 antagonist losartan (10 mg/kg per day) for 6 weeks.. Before treatment, the blood pressure was higher in Nx rats and increased further over time in Nx+13C4 rats. At the end of the study, Nx+13C4 rats exhibited increased serum creatinine, proteinuria and renal expression and excretion of TGF-beta1 and ET-1. ET-1 concentrations were greater in vascular and renal tissues, whereas the ETB receptor expression was reduced. Renal injuries were comprised of blood vessel hypertrophy, glomerular sclerosis, tubular atrophy and interstitial fibrosis, which was associated with increased alpha-smooth muscle actin expression. Treatment of uremic rats with the 1D11 antibody attenuated the increase in blood pressure and the decline in renal function. Losartan normalized the blood pressure and significantly attenuated the increase in serum creatinine and proteinuria. However, both treatments prevented renal TGF-beta1 and ET-1 overexpression, and prevented all renal histological injuries. The 1D11 antibody only improved ETB receptor expression.. Neutralization of TGF-beta attenuates hypertension and renal failure progression in uremic animals, in part, by preventing renal injury processes. These effects may be related to the modulation of the ET system, preventing renal ET-1 overproduction and the reduction of ETB receptor expression. Our data also suggest that TGF-beta1 is involved, at least in part, in the pathological effects related to angiotensin II in chronic renal failure.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antibodies; Aorta, Thoracic; Blood Pressure; Blotting, Northern; Blotting, Western; Creatinine; Endothelin-1; Gene Expression; Hypertension; Kidney; Losartan; Male; Neutralization Tests; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta; Uremia

To investigate the experimental therapeutic effects of iptakalim hydrochloride (Ipt) on renoprotection in spontaneously hypertensive rats.. 30 SHR were treated ig with Ipt 1, 3, 9 mg.kg(-1).d(-1), benazepril 3 mg.kg(-1).d(-1) once a day for 12 weeks. Age-matched WKY rats were used as normal control. The blood pressure, heart rates, proteinuria were assessed, and renal tissues were examined by light microscopy. The levels of blood and renal tissue ET-1 and TGF-beta1 were detected respectively by radioimmunoanalysis and enzyme linked immune absorption assay (ELISA).. During 12 weeks experimental period, the systolic blood pressure (SBP) and heart rates (HR) of the untreated SHR were increased progressively. Ipt (3, 9 mg.kg(-1).d(-1)) could decrease effectively and inhibit the increasing tendency of HR. In addition, Ipt (1, 3, 9 mg.kg(-1).d(-1)) reduced urinary proteinuria, alleviated obviously the small vascular remodeling of renal and decreased the levels blood and renal ET-1 and TGF-beta1. Ipt (3, 9 mg.kg(-1).d(-1)) alleviated obviously the small vascular remodeling of renal compared with Ipt (1 mg.kg(-1).d(-1)).. Ipt (1, 3, 9 mg.kg(-1).d(-1)) decreased SBP and protected the kidney of SHR. The renoprotection of Ipt may be involved in inhibiting of blood and renal tissue ET-1 and TGF-beta1.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Endothelin-1; Female; Heart Rate; Hypertension; Kidney; Male; Propylamines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Transforming Growth Factor beta

Previous studies demonstrated that adrenomedullin (AM) is metabolized by neutral endopeptidases and that the renal effect of AM is augmented by the inhibition of neutral endopeptidases. We have recently shown that the long-term administration of AM has renoprotective effects.. This study assessed the chronic renoprotective effects of AM combined with a vasopeptidase inhibitor in hypertensive rats and attempted to elucidate the mechanism involved.. We studied the following four groups: control Dahl salt-resistant (DR) rats, untreated Dahl salt-sensitive (DS) rats, omapatrilat (35 mg/kg per day)-treated DS rats; and human AM (500 ng/h) plus omapatrilat-treated DS rats. After 7 weeks' treatment, blood pressure, renal function, neurohumoral factors, gene expression levels, and histological findings were examined.. DS rats were characterized by increased blood pressure, decreased renal function, abnormal histological findings, and increased gene expression of collagen I and III, transforming growth factor beta (TGF-beta), and NADPH oxidase subunits (p40phox, p47phox, and gp91phox) in the renal cortex compared with DR rats. Compared with DS rats, omapatrilat significantly decreased systolic blood pressure (-26 mmHg), improved renal function, histological findings, and messenger RNA expression levels of collagen I, collagen III, and TGF-beta. Combined treatment with omapatrilat and AM further improved renal function, histological findings, and mRNA expression levels of collagen I, collagen III, and TGF-beta, without a further reduction in blood pressure. Only combined treatment decreased mRNA levels of p40phox, p47phox, and gp91phox. There were no differences in plasma AM or atrial natriuretic peptide levels among three DS groups.. Our results suggest that combined treatment with omapatrilat and AM provides additional renoprotective effects independent of blood pressure-lowering activity partly via inhibition of gene expressions of oxidative stress and extracellular matrix.

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Collagen Type I; Collagen Type III; Drug Therapy, Combination; Gene Expression; Humans; Hypertension; Kidney; Male; Oxidative Stress; Peptides; Protease Inhibitors; Pyridines; Rats; Rats, Inbred Dahl; Recombinant Proteins; RNA, Messenger; Thiazepines; Transforming Growth Factor beta

Vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-beta1) play an important role in angiogenesis. We wanted to determine if concentrations of growth factors in the coronary sinus (CS) and right atrium (RA) are higher in coronary artery disease patients with total occlusions than in those with partial occlusions. Fifty-one patients scheduled for coronary artery angiography were evaluated for possible recruitment. A 6F Goodale-Lubin catheter was used to collect blood from the CS and RA. Data for all but four patients were gathered successfully, leaving 47 study patients. The reviewer was blinded to growth factor data when interpreting coronary angiographic findings. Of the 47 enrolled patients, 32 had at least one diseased vessel, seven of whom had at least one major total epicardial coronary occlusion. In all 32 patients, the concentrations of VEGF in the CS were higher than those in the RA (31.5 +/- 2.7 vs 27.1 +/- 1.8 pg/mL; p = 0.005). Patients with total occlusions had higher VEGF concentrations in the CS than those with non-total occlusions (38.9 +/- 8.0 vs 29.5 +/- 2.6 pg/mL; p = 0.037). The differences in TGF-beta1 in the two groups were not statistically significant. The higher CS VEGF concentrations in patients with total occlusion indicate that VEGF may play a part in the development of angiogenesis.

Topics: Aged; Arterial Occlusive Diseases; Coronary Angiography; Coronary Disease; Coronary Stenosis; Coronary Vessels; Enzyme-Linked Immunosorbent Assay; Female; Heart Atria; Humans; Hypertension; Male; Middle Aged; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Studies were performed to test the hypothesis that the angiotensin-converting enzyme (ACE)/epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases (ERK) pathway, nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase/lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) pathway, and Rho-kinase pathway contribute to the pathogenesis of aldosterone/salt-induced hypertensive rats. Wistar rats were given 1% NaCl to drink and treated with one of the following combinations for 6 weeks: vehicle; aldosterone (0.75 microg/h); aldosterone plus a mineralocorticoid receptor antagonist, spironolactone (20 mg/kg/day); aldosterone plus an ACE inhibitor, imidapril (1 mg/kg/day); aldosterone plus an NAD(P)H oxidase inhibitor, apocynin (0.5 mmol/l); and aldosterone plus an Rho-kinase inhibitor, Y-27632 (3 mg/kg/day). Upregulated expression of ACE and EGFR and p44/p42ERK phosphorylation were suppressed by spironolactone or imidapril. Upregulated NAD(P)H oxidase subunits and LOX-1 expression were inhibited by spironolactone or apocynin. Increased expression of RhoA and Rho-kinase and myosin light chain phosphorylation were decreased by spironolactone or Y-27632. Moreover, these drugs effectively inhibited the vascular lesion formation, as measured by the medial thickness and level of perivascular fibrosis, and suppressed the expression of transforming growth factor-beta1, type I and III collagen, and monocyte chemoattractant protein-1 mRNA. Spironolactone may be useful as a cardioprotective agent to prevent cardiovascular remodeling via the ACE/EGFR/ERK, NAD(P)H oxidase/LOX-1, and Rho-kinase pathways.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Chemokine CCL2; Coronary Vessels; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Fibrillar Collagens; Gene Expression; Heart Ventricles; Hypertension; Imidazolidines; Intracellular Signaling Peptides and Proteins; Male; Mineralocorticoid Receptor Antagonists; NADPH Oxidases; Peptidyl-Dipeptidase A; Phosphorylation; Protein Serine-Threonine Kinases; Rats; Rats, Wistar; rho-Associated Kinases; rhoA GTP-Binding Protein; Scavenger Receptors, Class E; Signal Transduction; Sodium Chloride; Spironolactone; Transforming Growth Factor beta; Transforming Growth Factor beta1

Patients with type 2 diabetes and macroalbuminuria generally experience progressive glomerular filtration rate (GFR) decline despite angiotensin-converting enzyme inhibition (ACEI) and blood pressure (BP) control but this therapy generally stabilizes GFR in those without macroalbuminuria. Cigarette smoking exacerbates GFR decline in patients with type 2 diabetes and macroalbuminuria despite ACEI and BP control; whether this therapy prevents nephropathy progression in nonmacroalbuminuric type 2 diabetic smokers is unknown.. We determined the course of urine excretion of indices of renal injury that distinguished patients with type 2 diabetes with and without macroalbuminuria but with normal plasma creatinine who were prospectively followed 6 months while receiving ACEI and BP control. We compared this course in nonsmokers and smokers with normo-, micro-, and macroalbuminuria (n = 157) and in response to smoking cessation in a separate cohort (n = 80) with microalbuminuria.. Urine excretion of transforming growth factor beta-1 (UTGFbetaV) increased in macroalbuminuric but not in nonmacroalbuminuric nonsmokers and UTGFbetaV rate was higher in smokers than nonsmokers within each albuminuria group. In the separate microalbuminuric cohort, the rate of UTGFbetaV change for quitting smokers was not different from nonsmokers (0.093 versus -0.123 ng/g of creatine/week, P = not significant) but that for nonquitting smokers (0.970) was higher than nonsmokers (P = 0.017).. Patients with type 2 diabetes who are at high risk compared with low risk for nephropathy progression have progressive renal injury as measured by increasing UTGFbetaV. Cigarette smoking exacerbates renal injury in type 2 diabetes despite BP control and ACEI, but its cessation in those with microalbuminuria ameliorates the progressive renal injury caused by continued smoking.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Collagen Type IV; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Male; Middle Aged; Regression Analysis; Renal Insufficiency; Smoking; Smoking Cessation; Transforming Growth Factor beta

Peroxisome proliferator-activated receptor (PPAR)alpha is highly expressed in the heart. PPAR alpha may play a role in cardiac hypertrophy, but effects on cardiac function, inflammation, and fibrosis are unknown. We tested the hypothesis that the PPAR alpha activator fenofibrate prevents myocardial inflammation and fibrosis in angiotensin (Ang) II-infused rats.. Sprague Dawley rats received Ang II (120 ng/kg/min subcutaneously), fenofibrate (100 mg/kg/d p.o.), or Ang II + fenofibrate. After 7 d, systolic blood pressure (mmHg) was elevated (P < 0.01) in Ang II-infused rats (173 +/- 4) vs. controls (115 +/- 2) and reduced by fenofibrate (137 +/- 5). Electrophoretic mobility shift assay demonstrated that Ang II upregulated cardiac nuclear factor kappa B activity by 50%. Ang II significantly increased cardiac expression of vascular-cell adhesion molecule-1, platelet endothelial cell adhesion molecule, and intercellular adhesion molecule-1. Increases in expression of these inflammatory mediators were normalized by fenofibrate. Ang II-induced expression of transforming growth factor-beta 1, collagen deposition, and macrophage infiltration were partially prevented by fenofibrate.. The PPAR alpha activator fenofibrate prevented development of hypertension, and improved myocardial inflammation and collagen deposition in Ang II-infused rats. The hypolipidemic drug fenofibrate may be useful in prevention and treatment of myocardial disease associated with hypertension and hyperlipidemia.

Topics: Angiotensin II; Animals; Blood Pressure; Collagen; Electrocardiography; Fenofibrate; Fibrosis; Heart; Hypertension; Inflammation; Infusions, Intravenous; Intercellular Adhesion Molecule-1; Myocardium; NF-kappa B; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

Excessive myocardial fibrosis deteriorates diastolic function in hypertensive hearts. Involvement of macrophages is suggested in fibrotic process in various diseased situations. We sought to examine the role of macrophages in myocardial remodeling and cardiac dysfunction in pressure-overloaded hearts. In Wistar rats with suprarenal aortic constriction, pressure overload induced perivascular macrophage accumulation and fibroblast proliferation with a peak at day 3, decreasing to lower levels by day 28. Myocyte chemoattractant protein (MCP)-1 mRNA was upregulated after day 1, peaking at day 3 and returning to insignificant levels by day 28, whereas transforming growth factor (TGF)-beta induction was observed after day 3, with a peak at day 7, and remained relatively elevated at day 28. After day 7, concentric left ventricular (LV) hypertrophy developed, associated with reactive fibrosis and myocyte hypertrophy. At day 28, echocardiography showed normal LV fractional shortening but decreased ratio of early to late filling wave of transmitral Doppler velocity, and hemodynamic studies revealed elevated LV end-diastolic pressure, suggesting normal systolic but impaired diastolic function. Chronic treatment with an anti-MCP-1 monoclonal neutralizing antibody inhibited not only macrophage accumulation but also fibroblast proliferation and TGF-beta induction. Furthermore, the neutralizing antibody attenuated myocardial fibrosis, but not myocyte hypertrophy, and ameliorated diastolic dysfunction without affecting blood pressure and systolic function. In conclusion, roles of MCP-1-mediated macrophage accumulation are suggested in myocardial fibrosis in pressure-overloaded hearts through TGF-beta-mediated process. Inhibition of inflammation may be a new strategy to prevent myocardial fibrosis and resultant diastolic dysfunction in hypertensive hearts.

Topics: Animals; Antibodies, Monoclonal; Aortic Valve Stenosis; Chemokine CCL2; Diastole; Endomyocardial Fibrosis; Fibroblasts; Hypertension; Hypertrophy; Hypertrophy, Left Ventricular; Inflammation; Macrophages; Male; Models, Cardiovascular; Myocytes, Cardiac; Rats; Rats, Wistar; RNA, Messenger; Transforming Growth Factor beta

Renal perfusion pressure was servo-controlled chronically in rats to quantify the relative contribution of elevated arterial pressure versus angiotensin II (Ang II) on the induction of renal injury in Ang II-induced hypertension. Sprague-Dawley rats fed a 4% salt diet were administered Ang II for 14 days (25 ng/kg per minute IV; saline only for sham rats), and the renal perfusion pressure to the left kidney was continuously servo-controlled to maintain a normal pressure in that kidney throughout the period of hypertension. An aortic occluder was implanted around the aorta between the two renal arteries and carotid and femoral arterial pressure were measured continuously throughout the experiment to determine uncontrolled and controlled renal perfusion pressure, respectively. Renal perfusion pressure of uncontrolled, controlled, and sham kidneys over the period of Ang II or saline infusion averaged 152.6+/-7.0, 117.4+/-3.5, and 110.7+/-2.2 mm Hg, respectively. The high-pressure uncontrolled kidneys exhibited tubular necrosis and interstitial fibrosis, especially prominent in the outer medullary region. Regional glomerular sclerosis and interlobular artery injury were also pronounced. Controlled kidneys were significantly protected from interlobular artery injury, juxtamedullary glomeruli injury, tubular necrosis, and interstitial fibrosis as determined by comparing the level of injury. Glomerular injury was not prevented in the outer cortex. Transforming growth factor (TGF)-beta and active NF-kappaB proteins determined by immunohistochemistry were colocalized in the uncontrolled kidney in regions of interstitial fibrosis. We conclude that the preferential juxtamedullary injury found in Ang II hypertension is largely induced by pressure and is probably mediated through the TGF-beta and NF-kappaB pathway.

Topics: Angiotensin II; Animals; Aortic Valve Stenosis; Blood Pressure; Carotid Arteries; Femoral Artery; Fibrosis; Hypertension; Kidney; Kidney Tubular Necrosis, Acute; Male; NF-kappa B; Pressure; Rats; Rats, Sprague-Dawley; Renal Circulation; Sodium Chloride, Dietary; Transforming Growth Factor beta

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a potent natural inhibitor of hematopoietic stem cell proliferation which is degraded mainly by angiotensin-converting enzyme (ACE). In vitro, Ac-SDKP inhibits collagen production by cardiac fibroblasts; while in vivo it blocks collagen deposition in the left ventricle (LV) of rats with hypertension or myocardial infarction (MI). In addition, it reportedly prevents and reverses macrophage infiltration in the LV of rats with MI. We tested the hypothesis that when Ac-SDKP is infused at doses that cause plasma concentrations similar to those observed after ACE inhibition, it mimics the anti-inflammatory and antifibrotic effects of ACE inhibitors (ACEi) in the heart, and, further, that these effects are independent of changes in blood pressure.. Rats were divided into five groups: (1) controls, (2) Ang II (750 microg/kg per day, s.c.), (3) Ang II + captopril (100 mg/kg per day in drinking water), (4) Ang II + Ac-SDKP (400 microg/kg per day, s.c.), and (5) Ang II + Ac-SDKP (800 microg/kg per day, s.c.). We measured LV cell proliferation, inflammatory cell infiltration, cytokine expression, hypertrophy and fibrosis.. Plasma Ac-SDKP was five-fold higher in rats given ACEi and four- and ten-fold higher in rats given 400 and 800 microg/kg per day Ac-SDKP, respectively. ACEi significantly decreased Ang II-induced cell proliferation (Ki-67), LV macrophage/mast cell infiltration, transforming growth factor-beta, connective tissue growth factor and collagen deposition without affecting hypertension, LV hypertrophy or myocyte cross-sectional area, and these effects were mimicked by exogenous Ac-SDKP (400 microg/kg per day) which raised plasma Ac-SDKP to levels similar to ACEi. BP was not decreased by either ACEi or Ac-SDKP.. We concluded that Ac-SDKP may be an important mediator of the anti-inflammatory and antifibrotic effects of ACEi in hypertension independent of its hemodynamic effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Captopril; Cell Division; Collagen; Connective Tissue Growth Factor; Drug Therapy, Combination; Fibrosis; Growth Inhibitors; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Kidney; Macrophages; Male; Mast Cells; Monocytes; Myocardium; Myocytes, Cardiac; Oligopeptides; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

In order to study the association between myocardial fibrosis and inflammatory cell infiltration in the hypertensive heart, we investigated whether N(3,4-dimethoxycinnamoyl) anthranilic acid (tranilast), an anti-inflammatory drug, would suppress myocardial fibrosis via inhibition of inflammatory cell infiltration in deoxycorticosterone-acetate (DOCA) hypertensive rats.. Sprague-Dawley rats treated with DOCA combined with the addition of 1% NaCl and 0.2% KCl in the drinking water after left nephrectomy were given tranilast (100 mg/kg per day, n = 15) or vehicle (n = 15) for up to 4 weeks. Systolic blood pressure (SBP), amount of myocardial interstitial fibrosis, perivascular fibrosis and type I and III collagen, and mRNA expression of procollagen I (PI) and procollagen III (PIII), transforming growth factor (TGF)-beta1, type-1 plasminogen activator inhibitor (PAI-1), monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 were determined.. SBP was increased significantly 2 weeks after treatment with DOCA and salt. Myocardial interstitial fibrosis, perivascular fibrosis and collagen accumulation increased significantly 4 weeks after the treatment. Two weeks after the treatment with DOCA and salt, mRNA expression of PI and PIII, TGF-beta1, PAI-1, MCP-1 and IL-6 increased significantly. Although the SBP was similar in animals treated with tranilast or vehicle, monocyte/macrophage infiltration was suppressed, mRNA expression of TGF-beta1, PAI-1, MCP-1, IL-6, PI and PIII was attenuated, and myocardial fibrosis and collagen accumulation were suppressed in hypertensive animals receiving tranilast.. Myocardial fibrosis seen in DOCA/salt hypertensive rats might be associated with the inflammation/wound healing response. Tranilast suppresses both infiltration of monocytes/macrophages and myocardial fibrosis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Body Weight; Cardiomegaly; Chemokine CCL2; Collagen Type I; Collagen Type III; Desoxycorticosterone; Fibrosis; Hypertension; Interleukin-6; Macrophages; Male; Monocytes; Myocardium; Nephrectomy; Organ Size; ortho-Aminobenzoates; Plasminogen Activator Inhibitor 1; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sodium Chloride, Dietary; Transforming Growth Factor beta; Transforming Growth Factor beta1

To compare diverse effects of angiotensin II type 1 receptor antagonists (irbesartan) and angiotensin converting enzyme inhibitors (imidapril) on left ventricular remodeling in spontaneously hypertensive rats (SHR). Thirty male SHR were randomly divided into three groups: SHR-IR (treated with irbesartan, 50 mg/kg), SHR-IM (imidapril, 3 mg/kg), SHR-C (placebo). Ten male Wistar Kyoto rats (WKY) treated with placebo acted as the control. All treatments were administered once daily from 14 to 27 weeks of age. Imidapril and irbesartan have the similar inhibitor effects on blood pressure and left ventricular mass indexes in SHR. Despite both drugs suppressed ERK-1 protein expression, decreased cardiomyocytes apoptosis index, blocked collagen type I deposition, reduced TGF-beta(1) gene expression in SHR, imidapril elicits a stronger inhibitory effect. Irbesartan had little effect on MKP-1 protein expression, but imidapril decreased it significantly. As a result, the ERK-1/MKP-1 ratio in SHR-IR was significantly greater than that in SHR-IM (P < 0.05). These results suggest that the balance between MKP-1 and ERKs in myocardial tissue is important for cardiac cell proliferation and growth. They also indicate that the similar efficacy of antihypertensive treatment in reducing blood pressure does not predict the similar capacity to control the individual facet of left ventricular remodeling. Irbesartan is more effective in regressing the homeostasis between ERK-1 and MKP-1, however imidapril is superior in suppressing apoptosis and collagen synthesis in cardiac tissue.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Apoptosis; Biphenyl Compounds; Blood Pressure; Cell Cycle Proteins; Collagen Type I; Dual Specificity Phosphatase 1; Gene Expression; Heart Ventricles; Hypertension; Imidazoles; Imidazolidines; Immediate-Early Proteins; Irbesartan; Male; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Phosphoprotein Phosphatases; Protein Phosphatase 1; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Tetrazoles; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

Baroreflex and chemoreflex mechanisms play an important role in the dynamic adjustments of circulation and ventilation during daily life. Recently, we have observed atrophy and marked fibrosis in carotid glomus (CG) from old patients with carotid atherosclerosis who died following stroke. However, a possible limitation to interpretation of the results in that study was the superposition of arterial hypertension, atherosclerosis and aging in the patients. Taking this into account, spontaneously hypertensive rats (SHR) were used in order to study the CG in an experimental model with only hemodynamic stress.. To evaluate whether transforming growth factor-beta 1 (TGF-beta 1) and plasminogen activator inhibitor-1 (PAI-1) were involved in the extracellular matrix expansion in CG and autonomic ganglia (AG) in young, male, adult SHR.. Male SHR (n = 10) and Wistar-Kyoto (WKY) rats (n = 10) were used. Systolic blood pressure (SBP) was measured monthly up to 8 months of age, when the animals were killed; then, CG and AG were excised and processed for light microscopy and immunohistochemistry (TGF-beta 1, PAI-1 and protein S100).. SBP was highly correlated (P < 0.01) with CG fibrosis (r = 0.90), AG fibrosis (r = 0.96) and neuron number (r = -0.97). PAI-1 and TGF-beta 1 in CG and AG were significantly increased (P < 0.01) in SHR.. Severe damage was observed in CG and AG in SHR, which was, in addition, correlated with SBP. These results suggest that permanent high blood pressure produces remarkable lesions in these structures, even when the animals are not old. In view of the fact that CG and AG are of utmost importance in the genesis of cardiocirculatory reflexes, they might be considered as 'target organs' in arterial hypertension.

Topics: Animals; Blood Pressure; Carotid Body; Extracellular Matrix; Ganglia, Autonomic; Hypertension; Immunohistochemistry; Male; Plasminogen Activator Inhibitor 1; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Transforming Growth Factor beta; Transforming Growth Factor beta1

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and vascular endothelial growth factor (VEGF) may play key roles in atherosclerosis, and have been shown to regulate nitric oxide (NO) production. However, the molecular mechanisms by which betaxolol, a specific beta 1-antagonist, stimulates endothelial NO synthase (eNOS) expression associated with LOX-1 and VEGF are unclear. We hypothesized that in the left ventricle of Dahl salt-sensitive (DS) rats, betaxolol reduces production of LOX-1 by suppressing NAD(P)H oxidase p47phox expression; betaxolol stimulates eNOS production associated with expression of VEGF and LOX-1; and betaxolol inhibits adhesion molecule and signal transduction, which may be involved in cardiovascular remodeling.. After 5 weeks of feeding an 8% NaCl diet to 6-week-old DS rats (i.e. at 11 weeks of age), a distinct stage of concentric left ventricular hypertrophy was noted. Betaxolol (0.9 mg/kg per day) was administered to 6-week-old DS rats for 5 weeks until the onset of left ventricular hypertrophy stage.. Decreased expression of eNOS and VEGF in DS rats was increased by betaxolol. Upregulated LOX-1, NAD(P)H oxidase p47phox, intercellular and vascular cell adhesion molecule-1 expression and phosphorylations of p38 mitogen-activated protein kinase and p65 nuclear factor-kappa B activity were inhibited by betaxolol. Betaxolol administration resulted in significant improvement of cardiovascular remodeling and suppression of transforming growth factor-beta 1 and type I collagen expression.. These results suggest that cardioprotective effects of betaxolol may stimulate eNOS production associated with VEGF and LOX-1, and inhibit adhesion molecule and signal transduction in DS rats.

Topics: Animals; Antihypertensive Agents; Betaxolol; Collagen Type I; Hypertension; Intercellular Adhesion Molecule-1; Male; NADPH Oxidases; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; p38 Mitogen-Activated Protein Kinases; Phosphoproteins; Phosphorylation; Rats; Rats, Inbred Dahl; Receptors, LDL; Receptors, Oxidized LDL; Scavenger Receptors, Class E; Transcription Factor RelA; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A

Hypertension and anemia may be causes of left ventricular hypertrophy (LVH) in uremia but the molecular mechanism is not known. Uremia was induced in male Spraugue Dawley rats by 5/6 nephrectomy. The following groups of rats were studied for 6 weeks; uremic rats (U) fed ad. lib., control rats (C) pair-fed with U, U rats given hydralazine (100 mg/kg/day) (UH), U rats given erythropoietin (48 U/kg/week, i.p.) (UE). Both diastolic and mean arterial pressures are higher (P < 0.01) in U and UE compared with C whereas both pressures in UH were normalized. Hemoglobin in U was lower than in C, and was normalized in UE. U, UH and UE had higher heart weight/body weight ratios (HW/BW) as well as left ventricular weight/body weight ratios (LV/BW) compared with C (P < 0.01). Compared with U, UH has lower HW/BW and LV/BW (P < 0.05) and UE has normal HW/BW but lower LV/BW than U (P < 0.05). To see if the gene expression in uremic LVH is similar to that described in pressure overload LVH in which mRNA levels of angiotensin converting enzyme (ACE), transforming growth factor-beta1 (TGF-beta1), atrial natriuretic factors (ANF) and skeletal a- actin were increased, we measured these mRNA levels by Northern analysis. TGF-beta1, ACE and alpha-actin mRNA levels were not changed in all 4 groups. ANF mRNA in U and UE was increased 3 fold over C, and normalized in UH. Treatment of anemia with erythropoietin improved uremic LVH but did not change ANF mRNA; whereas treatment of hypertension with hydralazine normalized ANF mRNA but did not completely correct uremic LVH. Thus, gene expression in uremic LVH is distinct from that in pressure-overload LVH, suggesting that other unidentified factor(s) might be involved in uremic LVH.

Topics: Actins; Anemia; Animals; Atrial Natriuretic Factor; Erythropoietin; Gene Expression; Heart Ventricles; Hydralazine; Hypertension; Hypertrophy, Left Ventricular; Male; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Uremia

The increase in vessel wall strain in hypertension contributes to arterial remodeling by stimulating vascular smooth muscle cell (SMC) proliferation and collagen synthesis. Because L-proline is essential for the synthesis of collagen and cell growth, we examined whether cyclic strain regulates the transcellular transport of L-proline by vascular SMC.. Cultured rat aortic SMCs were subjected to mechanical strain using the Flexercell 3000 Strain Unit.. Cyclic strain increased L-proline transport in a time- and strain-degree-dependent manner that was inhibited by cycloheximide or actinomycin D. Kinetic studies indicated that cyclic strain-induced L-proline uptake was mediated by an increase in transport capacity independent of any change in the affinity for L-proline. Cyclic strain stimulated the expression of system A amino acid transporter 2 mRNA in a time-dependent fashion that paralleled the increase in L-proline transport. Cyclic strain also induced the release of transforming growth factor-beta1 in a time- and strain-dependent manner. Moreover, conditioned media from SMCs exposed to cyclic strain stimulated the transport of L-proline in control, static SMCs and this was significantly attenuated by a transforming growth factor-beta1 neutralizing antibody.. These results demonstrate that cyclic strain stimulates L-proline transport by inducing system A amino acid transporter 2 gene expression through the autocrine release of transforming growth factor-beta1. The ability of cyclic strain to induce system A amino acid transporter 2 expression may promote arterial remodeling in hypertension by providing vascular SMCs with the necessary intracellular levels of L-proline required for collagen synthesis and cell growth.

Topics: Amino Acid Transport System A; Animals; Aorta, Thoracic; Autocrine Communication; Blood Pressure; Cells, Cultured; Hypertension; Muscle, Smooth, Vascular; Proline; Rats; RNA, Messenger; Stress, Mechanical; Transforming Growth Factor beta; Transforming Growth Factor beta1

Peripheral vasculature undergoes extensive vascular remodeling in the hypertensive state. Regulation of extracellular matrix turnover by the matrix metalloproteinase (MMP) system is an important step in the vascular remodeling process. However, the expression pattern of the vascular MMP system in human hypertension remained unknown.. Internal mammary artery specimens were obtained from normotensive (n = 13) and hypertensive (n = 19) patients undergoing coronary artery bypass grafting surgery. Zymographic analysis indicated a threefold decrease in total gelatinolytic activity of MMP-2 and MMP-9 in hypertension. MMP-1 activity was also decreased by fourfold without a significant change in protein levels. Tissue levels of extracellular matrix inducer protein (EMMPRIN), MMP activator protein (MT1-MMP), MMP-1, MMP-2, and MMP-9, as well as tissue inhibitors of MMPs (TIMP-1 and TIMP-2) were assessed by immunoblotting and yielded a significant decrease in MMP-9, EMMPRIN, and MT1-MMP levels in hypertension. In addition, measurement of plasma markers of collagen synthesis (procollagen type I amino-terminal propeptide [PINP]) and collagen degradation (carboxy-terminal telopeptide of collagen type I [ICTP]) indicated no difference in PINP levels but suppressed degradation of collagen in hypertension. Evaluation of profibrotic growth factors demonstrated higher levels of fibroblast growth factor (FGF)-2 in tissue preparations from hypertensive patients but no difference in transforming growth factor-beta1 levels.. These findings demonstrate that not only MMP-1 and MMP-9, but MMP inducer and activator proteins are also downregulated in the hypertensive state. Augmented FGF-2 levels may contribute to parallel decreases in MMP activity and MMP induction system resulting in enhanced collagen deposition in hypertension.

Topics: Antigens, CD; Antigens, Neoplasm; Basigin; Coronary Artery Bypass; Down-Regulation; Extracellular Matrix; Female; Fibroblast Growth Factor 2; Humans; Hypertension; Male; Mammary Arteries; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Matrix Metalloproteinases, Membrane-Associated; Metalloendopeptidases; Middle Aged; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta; Transforming Growth Factor beta1

The therapeutic efficacy of angiotensin II receptor antagonist, losartan, was studied in patients with nonalcoholic steatohepatitis (NASH). Seven patients with both NASH and hypertension were treated with losartan (50 mg/d) for 48 weeks. Treatment with losartan resulted in a significant decrease in blood markers of hepatic fibrosis, plasma TGF-beta1 and serum ferritin concentration concurrently with an improvement in serum aminotransferase levels. Histological assessment showed improvement of hepatic necroinflammation in five patients, reduction of hepatic fibrosis in four patients, and disappearance of iron deposition in two patients. No side effect of treatment was noted at any time during the study. In conclusion, the present data raise the possibility that an angiotensin II receptor antagonist may be therapeutically efficacious for NASH.

Topics: Adult; Angiotensin Receptor Antagonists; Biomarkers; Fatty Liver; Female; Ferritins; Hepatitis; Humans; Hypertension; Iron; Liver; Liver Cirrhosis; Losartan; Male; Middle Aged; Necrosis; Osmolar Concentration; Transaminases; Transforming Growth Factor beta; Transforming Growth Factor beta1

To evaluate the plasma TGF-beta1 level in erectile dysfunction (ED) patients of various causes.. Sixty-two patients with ED and 26 potent men were subjected to the study. Based on multidisciplinary work-ups, including medical history, physical examinations, blood tests with lipid profile and hormones, penile duplex Doppler ultrasonogram and neurophysiological tests, causes for ED were classified as psychogenic (n=15), neurogenic (n=16) and vasculogenic (n=31). The plasma TGF-beta1 level was measured by the ELISA method.. The plasma TGF-beta1 level was significantly increased in the ED group (6.7+/-4.9 ng/mL), compared to the control (4.0 +/-2.1 ng/mL) (P<0.01). In the ED groups, there was a significant increase in the vasculogenic group (9.0 +/-5.5 ng/mL), compared to the psychogenic (3.8 +/-1.8 ng/mL) and neurogenic groups (4.8+/-3.2 ng/mL) (P<0.01). Of the vascular risk factors, both the smoking (7.5 +/-4.7 ng/mL) and dyslipidemia groups (7.4+/-4.4 ng/mL) showed significantly increased plasma TGF-beta1 levels, compared to the non-smokers (5.5+/-2.8 ng/mL), and those without dyslipidemia (4.8+/-2.8 ng/mL) (P<0.05).. Vascular risk factors are associated with an elevated plasma TGF-beta1 level, which may contribute to cavernous fibrosis and ED.

Topics: Adult; Aged; Arteriosclerosis; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Erectile Dysfunction; Female; Humans; Hyperlipidemias; Hypertension; Impotence, Vasculogenic; Male; Middle Aged; Penis; Risk Factors; Smoking; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ultrasonography

To explore the effect of perindopril on renal interstitial fibrosis of spontaneously hypertensive rats and on the expression of transforming growth factor-beta1.. Spontaneously hypertensive rats at the age of 9 weeks were randomly assigned to 2 groups: Spontaneously hypertensive rats (SHR, vehicle once daily, n = 10) and Treament-SHR (T-SHR, perindopril, 4 mg/(kg x d), per day PO, n = 10). Wistar-Kyoto rats (WKY, n = 7) were served as controls. After 10 weeks of treatment, the serum concentration of TGF-beta1, collagen type I, III and TGF-beta1 in the renal interstitum and renal mRNA levels of TGF-beta1 were detected.. There were no significant differences in the serum TGF-beta1 levels among the 3 groups (P > 0.05). Immunohistochemical studies revealed a significant interstitial accumulation of collagens I, III and TGF-beta1 in SHR compared with those in WKY (P < 0.01 or P < 0.05). These changes in SHR were significantly ameliorated by the administration of perindopril (P < 0.01 or P < 0.05). In SHR, renal TGF-beta1 mRNA expression was increased significantly compared with that in WKY (P < 0.01), but perindopril decreased it to the normal levels of WKY (P > 0.05). The increased expression of TGF-beta1 was blocked by perindopril. The expressions of collagens I and III in renal interstitum significantly correlated with the accumulation of TGF-beta1 in the renal (r = 0. 734, r = 0.762, respectively; P < 0.01).. The tubulointerstitial fibrosis of spontaneously hypertensive rats is mediated by an increased level of TGF-beta1 in the renal tissue, and perindopril may decrease the expression of TGF-beta1 to ameliorate the tubulointerstitial fibrosis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Collagen Type I; Collagen Type III; Female; Hypertension; Kidney; Male; Nephrosclerosis; Perindopril; Random Allocation; Rats; Rats, Inbred SHR; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

Albumin excretion is modulated post-filtration by lysosomal processing that produces a spectrum of albumin-derived material in urine, much of which is not detected by conventional immunoassays. This study aimed to determine the efficacy of ramipril treatment (+ RAM) after 24 weeks on total albumin excretion (intact plus albumin-derived peptides) in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with (d) and without (c) diabetes.. Intact albumin excretion was analysed by radioimmunoassay and total albumin excretion was analysed by measuring radioactivity derived from circulating [ C]albumin. Renal lysosomal activity was determined by urinary [ H]dextran sulphate desulphation. Renal transforming growth factor-beta 1 (TGF-beta 1), TGF-beta inducible gene-h3 (beta ig-h3) and angiotensinogen mRNA production were analysed by real time reverse transcriptase-polymerase chain reaction.. Hypertension (SHR-c and SHR-d) resulted in a significant increase in intact albumin excretion, which was significantly reduced by ramipril treatment (P < 0.05 for SHR-c + RAM and 0.001 for SHR-d + RAM compared to non-treated). This was accompanied by a significant decrease in blood pressure (P < 0.001 for SHR-c + RAM and SHR-d + RAM), renal beta ig-h3 mRNA production (P < 0.05 for SHR-c + RAM and SHR-d + RAM), and an increase in lysosomal activity. Diabetes (WKY-d and SHR-d) primarily caused a significant increase in total albumin excretion, predominantly in the form of albumin-derived fragments in the WKY-d group and intact albumin in the SHR-d group. Ramipril treatment reduced total albumin excretion in the WKY-d + RAM group (P < 0.001).. Ramipril prevents increases in both intact albumin and total albumin excretion in hypertensive and diabetic states, respectively.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Diabetes Mellitus; Extracellular Matrix Proteins; Hypertension; Lysosomes; Male; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

Recently, we have shown that in rats with a suprarenal abdominal aortic constriction (AC), pressure overload induces early perivascular fibro-inflammatory changes (transforming growth factor [TGF]-beta induction and fibroblast proliferation) within the first week after AC and then causes the development of cardiac remodeling (myocyte hypertrophy and reactive myocardial fibrosis) associated with diastolic dysfunction. Intercellular adhesion molecule (ICAM)-1 is implicated in the recruitment of leukocytes, especially macrophages, in various inflammatory situations. Thus, we sought to investigate the causal relation of ICAM-1 to macrophage recruitment and cardiac remodeling in AC rats. In AC rats, immunoreactive ICAM-1 was observed transiently on endothelial cells of the intramyocardial coronary arterioles after day 1, with a peak at day 3, returning to baseline by day 7. Also, ED1+ macrophage accumulation was found in the area adjacent to the arteries expressing ICAM-1. Chronic treatment with an anti-ICAM-1 neutralizing antibody, but not with control IgG, remarkably reduced the accumulations of macrophages and proliferative fibroblasts and inhibited the upregulation of TGF-beta expression. Furthermore, the neutralizing antibody significantly prevented myocardial fibrosis without affecting arterial pressure and left ventricular and myocyte hypertrophy. In conclusion, ICAM-1 expression was induced by pressure overload in the intramyocardial arterioles, and triggered perivascular macrophage accumulation. In pressure-overloaded hearts, a crucial role in ICAM-1-mediated macrophage accumulation was suggested in the development of myocardial fibrosis, through TGF-beta induction and fibroblast activation.

Topics: Animals; Antibodies, Monoclonal; Blood Pressure; Cardiomegaly; Cell Division; Cell Movement; Constriction; Coronary Vessels; Fibroblasts; Fibrosis; Hypertension; Inflammation; Intercellular Adhesion Molecule-1; Macrophages; Male; Myocytes, Cardiac; Pressure; Rats; Rats, Wistar; Transforming Growth Factor beta

Although it is known that diabetic nephropathy is accelerated by hypertension, the mechanisms involved in this process are not clear. In this study we aimed to clarify these mechanisms using male Wistar fatty rats (WFR) as a type 2 diabetic model and male Wistar lean rats (WLR) as a control. Each group was fed a normal or high sodium diet from the age of 6 to 14 weeks. We determined the blood pressure and urinary albumin excretion (UAE). At the end of the study, the expressions of mitogen-activated protein kinases (MAPK) and transforming growth factor-beta1 (TGF-beta1) were examined in the isolated glomeruli by Western blot analysis, and the number of glomerular lesions was determined by conventional histology. High sodium load caused hypertension and a marked increase in UAE in the WFR but not in the WLR. Glomerular volume was increased in the hypertensive WFR. There was no difference among the four groups in the expression of c-Jun-NH2-terminal kinase (JNK). In contrast, the expressions of extracellular signal-regulated kinase 1/2 (ERK1/2) and its upstream regulator, MAPK/ERK kinase 1 (MEK1), were augmented in the hypertensive WFR. Expression of p38 MAPK was increased in the normotensive WFR, and further enhanced in the hypertensive WFR. Moreover, administration of high sodium load to WFR augmented the expression of TGF-beta1. In conclusion, systemic hypertension in WFR accelerates the diabetic nephropathy in type 2 diabetes via MEK-ERK and p38 MAPK cascades. TGF-beta1 is also involved in this mechanism.

Topics: Albuminuria; Animals; Blotting, Western; Body Weight; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Hemodynamics; Hypertension; Kidney; Kidney Glomerulus; Male; Mitogen-Activated Protein Kinases; Organ Size; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-jun; Rats; Rats, Wistar; Sodium; Transforming Growth Factor beta

Mesangial matrix deposition is the hallmark of hypertensive and diabetic glomerulopathy. At similar levels of systemic hypertension, Dahl salt-sensitive but not spontaneously hypertensive rats (SHR) develop glomerular hypertension, which is accompanied by upregulation of transforming growth factor beta1 (TGF-beta1), mesangial matrix expansion, and sclerosis. GLUT-1 is ubiquitously expressed and is the predominant glucose transporter in mesangial cells. In mesangial cells in vitro, GLUT-1 overexpression increases basal glucose transport, resulting in excess fibronectin and collagen production. TGF-beta1 has been shown to upregulate GLUT-1 expression. We demonstrated that in hypertensive Dahl salt-sensitive (S) rats fed 4% NaCl (systolic blood pressure [SBP]: 236+/-9 mm Hg), but not in similarly hypertensive SHR (SBP: 230+/-10 mm Hg) or their normotensive counterparts (Dahl S fed 0.5% NaCl, SBP: 145+/-5 mm Hg; and Wistar-Kyoto, SBP: 137+/-3 mm Hg), there was an 80% upregulation of glomerular GLUT-1 protein expression (P< or =0.03). This was accompanied by a 2.7-fold upregulation of TGF-beta1 protein expression in glomeruli of DSH compared with DSN rats (P=0.02). TGF-beta1 expression was not upregulated and did not differ in the glomeruli of Wistar-Kyoto and SHR rats. As an in vitro surrogate of the in vivo hemodynamic stress imposed by glomerular hypertension, we used mechanical stretching of human and rat mesangial cells. We found that after 33 hours of stretching, mesangial cells overexpressed GLUT-1 (40%) and showed an increase in basal glucose transport of similar magnitude (both P< or =0.01), which could be blocked with an anti TGF-beta1-neutralizing antibody. These studies suggest a novel link between hemodynamic and metabolic factors that may cooperate in inducing progressive glomerular injury in conditions characterized by glomerular hypertension.

Topics: Animals; Biological Transport; Cells, Cultured; Glomerular Mesangium; Glucose; Glucose Transporter Type 1; Hemodynamics; Humans; Hypertension; Hypertension, Renal; Immunoblotting; Immunohistochemistry; Kidney Cortex; Kidney Glomerulus; Male; Monosaccharide Transport Proteins; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Rats, Inbred WKY; Stress, Mechanical; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

The study of salt-sensitive hypertension has been facilitated by development of genetic models, especially the Dahl/Rapp salt-sensitive (S) rat. S rats rapidly become hypertensive after initiation of a diet containing 8.0% NaCl and subsequently develop arteriolonephrosclerosis and renal failure, whereas the salt-resistant (R) strain remains normotensive on the same diet. The purpose of the present study was to use these strains to demonstrate the interactions between transforming growth factor-beta1 (TGF-beta1) and nitric oxide (NO). Young, male S and R rats were fed for 4 days diets that contained either 0.3 or 8.0% NaCl. An increase in dietary salt increased kinase activities of both p38 MAPK and p42/44 MAPK in cytoplasmic extracts from aortic rings and isolated glomeruli from both strains. Inhibition of either pathway with PD-098059 or SB-203580 decreased production of TGF-beta1 and nitrate plus nitrite (NOx). In both strains, production of active TGF-beta1 and NOx linearly correlated. Incubation of aortic rings and isolated glomeruli with the NO donor NOR3 decreased TGF-beta1 levels, whereas the NO synthase inhibitor Nomega-nitro-l-arginine methyl ester increased production. The inhibitory effect of NO on production of TGF-beta1 was reduced in preparations from S rats. Although a close interrelationship existed between TGF-beta1 and NO in both strains, production of TGF-beta1 was increased in prehypertensive S rats and was further exaggerated with the increase in dietary salt intake. Augmented vascular and glomerular production of TGF-beta1 and diminished NO may contribute to the development of hypertensive nephrosclerosis in S rats.

Topics: Animals; Aorta; Enzyme Inhibitors; Hypertension; In Vitro Techniques; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Nitrates; Nitric Oxide; Nitrites; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Rats; Rats, Inbred Dahl; Serine; Sodium Chloride, Dietary; Transforming Growth Factor beta; Transforming Growth Factor beta1

Cardiac mast cells participate in myocardial dysfunction, but the mechanisms are presently unknown.. By examining spontaneously hypertensive rats (SHRs) during their entire lifespan, we attempted to define the role of mast cells in the induction of cardiac hypertrophy and transition to heart failure.. By contrast to normotensive littermates, hearts of newborn SHRs already contained mast cells. In the prehypertensive (2-week-old) SHRs, the increased expression of c-kit and soluble stem cell factor correlated with an increased number of cardiac mast cells. The mast cells contained tumour necrosis factor-alpha which, together with nuclear factor kappa-B (NF-kappaB) and interleukin (IL)-6, was significantly induced in the prehypertensive SHRs. Stimulation of cardiac mast cells with compound 48/80 in an ex-vivo Langendorff heart perfusion system resulted in increased expression of nuclear factor Kappa-B (NF-kappaB) (four-fold) and IL-6 (nine-fold) mRNA in the left ventricles of adult rat hearts. In the presence of an inhibitor of mast cell degranulation, disodium cromoglycate, the induced expression of NF-kappaB and IL-6 was inhibited. In the late hypertensive stage, the hearts of SHRs with advanced cardiac hypertrophy (12-month-old) and heart failure (20-month-old) had significantly increased levels of transforming growth factor (TGF)-beta1 and basic fibroblast growth factor (bFGF), and displayed increased myocardial fibrosis. Activated mast cells were a major source of TGF-beta1 and bFGF, and localized to areas of myocardial fibrosis.. By synthesizing and secreting prohypertrophic cytokines and profibrotic growth factors, cardiac mast cells participate in the induction of cardiac hypertrophy and cardiac fibrosis, which are the key steps in the transition to heart failure.

Topics: Animals; Body Weight; Cardiomegaly; Chemotactic Factors; Fibroblast Growth Factor 2; Gene Expression; Heart Failure; Hypertension; Interleukin-6; Male; Mast Cells; Myocardium; NF-kappa B; Organ Size; p-Methoxy-N-methylphenethylamine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Recently, we have shown that pressure overload transiently induces transforming growth factor-beta-mediated fibroblast proliferation and reactive myocardial fibrosis that extends from the perivascular space. However, the upper stream event of transforming growth factor-beta induction has remained unknown. Thus, we sought to determine whether angiotensin II mediates the fibrotic process in pressure-overloaded hearts. Male Wistar rats were administered orally everyday 0.1 mg/kg per day of candesartan, an angiotensin type-1 receptor blocker, or the vehicle from Day 7, and underwent a suprarenal aortic constriction (AC) at Day 0. This dose was the maximum dose of candesartan that does not induce the depressor effect in AC rats. In AC+ vehicle (control) rats, pressure overload induced myocardial transforming growth factor-beta expression and perivascular fibroblast proliferation at Day 3 and thereafter left ventricular hypertrophy associated with cardiomyocyte hypertrophy and perivascular fibrosis. AC+ candesartan rats showed suppressed transforming growth factor-beta expression and reduced number of proliferating fibroblasts, while not changing arterial pressure. Furthermore, perivascular fibrosis, but not myocyte hypertrophy, was significantly inhibited associated with reduced collagen mRNA expression. In conclusion, angiotensin II may play a role in reactive myocardial fibrosis in pressure-overloaded hearts, through the mechanism independent of hemodynamic change.

Topics: Administration, Oral; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Aorta; Benzimidazoles; Biphenyl Compounds; Collagen; Constriction; Disease Models, Animal; Dose-Response Relationship, Drug; Endomyocardial Fibrosis; Fibroblasts; Hypertension; Male; Myocytes, Cardiac; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Tetrazoles; Time Factors; Transforming Growth Factor beta; Ventricular Remodeling

Angiotensin-converting enzyme inhibitors have been shown to reduce morbidity and mortality in patients with heart failure. The angiotensin type-1 blocking and cardioprotective properties of perindopril and enalapril were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Enalapril at 20 mg/kg showed the same angiotensin type-1 blocking action as perindopril at 2 mg/kg in rats with heart failure. Twenty-eight days after immunization, surviving Lewis rats (90/120 = 75%) were divided into six groups and administered perindopril at 0.02, 0.2 and 2 mg/kg per day (Groups P0.02, P0.2 and P2), enalapril at 2 and 20 mg/kg per day (Groups E2 and E20) or vehicle alone (Group V, all groups n = 15). After oral administration for 1 month, four of 15 (27%) rats in Group V, and two (13%) in Groups P0.02 and E2 died. None of the animals in Groups P0.2, P2 and E20, or normal rats (Group N) died. Although both angiotensin-converting enzyme inhibitors improved ventricular function in a dose-dependent manner, the left ventricular end-diastolic pressure and area of myocardial fibrosis were lower, and +/- dP/dt was higher in Group P2 (4.9 +/- 0.6 mmHg, 7.5 +/- 1.4% and +2651 +/- 254/-2622 +/- 189 mmHg/s, respectively) than in Group V (16.7 +/- 1.3, 36 +/- 2.6 and +2659 +/- 176/-2516 +/- 205, respectively) and Group E20 (7.5 +/- 2.5, 15.6 +/- 2.0 and +2018 +/- 110/-2097 +/- 102, respectively). Although the expression levels of transforming growth factor-beta1 and collagen-III mRNA in Group V (36.3 +/- 5.7 and 157.6 +/- 12.7%) were significantly higher than those in Group N (19.6 +/- 3.0 and 65.2 +/- 1.5%, both p < 0.01), they were reduced in Group P2 (21.4 +/- 5.9 and 75.2 +/- 9.3%, both p < 0.01). These results suggest that although enalapril can block increases in blood pressure caused by circulating angiotensin type-1, perindopril at 2 mg/kg may confer greater protection than enalapril at 20 mg/kg against injury from the renin-angiotensin system in heart failure.

Topics: Administration, Oral; Angiotensin I; Animals; Cardiomyopathy, Dilated; Collagen Type III; Disease Models, Animal; Dose-Response Relationship, Drug; Enalapril; Endomyocardial Fibrosis; Gene Expression; Heart Failure; Hemodynamics; Hypertension; Infusions, Intravenous; Male; Pericardial Effusion; Perindopril; Rats; Rats, Inbred Lew; RNA, Messenger; Survival Rate; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Dysfunction, Left; Ventricular Pressure

Serum transforming growth factor-beta (TGF-beta1) production was estimated for 10 patients with essential hypertension, 12 patients with glomerulonephritis (5 hypertensive and 7 normotensive) and 10 healthy controls. The glomerulonephritis group received angiotensin-converting enzyme inhibitor captopril 25-75 mg/day for 4 weeks. Blood urea, serum creatinine, 24-hour urinary protein and serum TGF-beta1 were then re-estimated. Urea and creatinine were significantly higher in the hypertension and glomerulonephritis groups than in the controls and also higher in the glomerulonephritis group than the hypertension group. TGF-beta1 was significantly higher in the glomerulonephritis groups than in the control and hypertension groups. TGF-beta1 and 24-hour urinary protein were significantly reduced in the glomerulonephritis group.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Urea Nitrogen; Captopril; Case-Control Studies; Chronic Disease; Creatinine; Female; Glomerulonephritis; Humans; Hypertension; Immunoassay; Male; Middle Aged; Proteinuria; Transforming Growth Factor beta; Transforming Growth Factor beta1; Treatment Outcome

The mechanism and treatment of hypertensive systolic heart failure are not well defined. We compared the effect of an angiotensin-converting enzyme inhibitor (cilazapril, 10 mg/kg), an angiotensin receptor blocker (candesartan, 3 mg/kg), a calcium channel blocker (benidipine, 1, 3 or 6 mg/kg), and the same calcium channel blocker combined with renin-angiotensin blockers on systolic heart failure in Dahl salt-sensitive (DS) rats. DS rats were fed an 8% Na diet from 6 weeks of age and then subjected to the above drug treatments. Benidipine (1 mg/kg), cilazapril, and candesartan had compatible hypotensive effects and similar beneficial effects on cardiac hypertrophy, gene expression, and survival rate. The combination of benidipine with cilazapril or candesartan was found to have no additional beneficial effects on the above parameters, with the exception of a reduction in atrial natriuretic polypeptide gene expression. On the other hand, candesartan normalized serum creatinine, but serum creatinine was unaffected by either benidipine at 1 or 3 mg/kg or cilazapril. Further, the combined use of benidipine and either candesartan or cilazapril resulted in an additional reduction of urinary albumin excretion in DS rats. Thus systolic heart failure in DS rats is mainly mediated by hypertension, while renal dysfunction of DS rats is due to both hypertension and the AT1 receptor itself. These findings suggest that the combination of a calcium channel blocker with an AT1 receptor blocker or ACE inhibitor may be more effective in treating the renal dysfunction associated with systolic heart failure than monotherapy with either agent alone. However, further studies will be needed before reaching any definitive conclusion on the efficacy of this combination therapy in patients with heart failure.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Cilazapril; Dihydropyridines; Drug Therapy, Combination; Heart Failure; Hypertension; Kidney; Natriuretic Peptide, Brain; Organ Size; Rats; Receptor, Angiotensin, Type 1; RNA, Messenger; Survival Rate; Systole; Transforming Growth Factor beta

To investigate the effects of the mixed endothelin receptor antagonist, bosentan, combined with the long-acting calcium channel blocker, amlodipine, compared to the angiotensin-converting enzyme inhibitor, cilazapril, on the progressive renal injury in spontaneous hypertensive rats (SHR) with diabetes.. Diabetic hypertensive rats (SHR-DM) were induced by streptozotozin injected in male SHR (7-week-old),and divided into an untreated and three treated groups: 1) cilazapril treated group; 2) bosentan+amlodipine treated group; and 3) amlodipine treated group. Wistar Kyoto rats (WKY) and SHR rats served as normotensive and hypertensive control, respectively. The mean arterial blood pressure, renal function, endothelin and angiotensin II levels as well as the protein expression of renal extracellular matrix components and transforming growth factor (TGF)-beta1 were determined at the end of the 4th week.. Mean arterial blood pressure significantly increased in SHR and SHR-DM rats compared to WKY rats. All the therapies reduced the blood pressure to normal levels. However, the enhanced urinary protein excretion, the decreased creatinine clearance as well as the increased plasma and intrarenal endothelin and angiotens in II levels were found in the untreated SHR-DM and prevented by treatment with bosentan+amlodipine and cilazapril. Similarly, these two kinds of therapies in SHR-DM abolished the overexpression of renal TGF-beta1 by Western blot analysis and reduced the accumulation of collagen type IV, laminin and fibronectin proteins by an immunochemical approach. Amlodipine monotherapy had no detectable effects on the above parameters.. Bosentan combined with amlodipine can offer similar renoprotective effects on that of cilazapril and may be a potent therapy to attenuate renal injury by reducing renal protein levels of TGF-beta1 in diabetes with a hypertensive state.

Topics: Amlodipine; Angiotensin II; Animals; Bosentan; Calcium Channel Blockers; Collagen Type IV; Diabetic Nephropathies; Drug Therapy, Combination; Endothelin Receptor Antagonists; Hypertension; Kidney; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sulfonamides; Transforming Growth Factor beta; Transforming Growth Factor beta1

The possible role of calcineurin in the attenuation of cardiac hypertrophy and fibrosis by blockade of the angiotensin II type 1 (AT1) receptor was investigated in Dahl salt-sensitive (DS) rats. The effect of the calcineurin inhibitor FK506 was also studied. DS rats progressively developed severe hypertension when fed a diet containing 8% NaCl from 7 weeks of age. In addition, marked cardiac hypertrophy and fibrosis were apparent and the activity of calcineurin and its mRNA expression in the myocardium was increased in these animals at 12 weeks in comparison with age-matched Dahl salt-resistant rats. The abundance of angiotensin-converting enzyme (ACE) and transforming growth factor (TGF)-beta1 mRNAs was also increased in the hearts of DS rats at 12 weeks. Treatment of DS rats with a non-antihypertensive dose of the selective AT1 receptor blocker candesartan (1 mg/kg per day) or FK506 (0.1 mg/kg per day) from 7 to 12 weeks attenuated both calcineurin activity and its mRNA expression in the heart, as well as the development of cardiac hypertrophy and fibrosis, without affecting cardiac function. Treatment with candesartan, but not FK506, prevented the upregulation of ACE and TGF-beta1 gene expression. Both candesartan and FK506 prevented the load-induced induction of fetal-type cardiac genes. These results demonstrate that AT1 receptor blockade attenuates the development of cardiac hypertrophy and fibrosis as well as the activation of calcineurin, without an antihypertensive effect, in rats with salt-sensitive hypertension. Calcineurin may be downstream from TGF-beta1 in AT1 receptor-mediated angiotensin II signaling in vivo.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Calcineurin; Cardiomegaly; Echocardiography; Fibrosis; Gene Expression Regulation; Hypertension; Male; Myocardium; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; RNA, Messenger; Stress, Mechanical; Tacrolimus; Tetrazoles; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor-beta1 (TGF-beta1) has been demonstrated to be overexpressed in hypertension. Leptin, an adipocyte product, has been shown to play a role in obesity-related hypertension and in vitro studies demonstrated a biologic interaction between leptin and TGF-beta1. Thus, we evaluate a possible in vivo association between TGF-beta1, body mass index (BMI), and leptin circulating levels in hypertensive subjects.. Blood samples for fasting leptin and TGF-beta1, were evaluated in 29 overweight, 46 obese, and 29 nonobese hypertensive patients before and after a 12-week calorie-restricted diet. Monocyte cultures were used for in vitro experiments.. Transforming growth factor-beta1 was significantly elevated in hypertensive obese patients (n = 46) as compared with TGF-beta1 levels of hypertensive patients with normal BMI (n = 29) (8. 9 +/- 3 ng/mL v 4.4 +/- 2; P < .001). The circulating levels of TGF-beta1 were associated with BMI and leptin levels in an univariate analysis (r = 0.59, P < .0001; r = 0.62, P < .0001, respectively) and these associations were still present after stepwise multivariate analysis. Weight loss of 10% produced a parallel decrease in TGF-beta1 (from 8.9 +/- 3 ng/mL to 5.3 +/- 2.8 ng/mL; P < .01) and leptin levels (from 30 +/- 24 ng/mL to 17 +/- 14; P < .05). In vitro experiments showed that leptin is able to induce a dose-dependent increase in TGF-beta1 production and mRNA expression in human monocyte cultures.. Our data indicate that TGF-beta1 levels are positively associated with BMI and leptin levels in hypertensive patients and suggest that adipose tissue may be an important determinant of TGF-beta1 levels possibly by a leptin-dependent pathway.

Topics: Adult; Blood Pressure; Body Mass Index; Female; Gene Expression; Humans; Hypertension; In Vitro Techniques; Leptin; Male; Middle Aged; Obesity; Regression Analysis; RNA, Messenger; Transforming Growth Factor beta; Weight Loss

Guanylyl cyclase (GC)-A, a natriuretic peptide receptor, lowers blood pressure and inhibits the growth of cardiac myocytes and fibroblasts. Angiotensin II (Ang II) type 1A (AT1A), an Ang II receptor, regulates cardiovascular homeostasis oppositely. Disruption of GC-A induces cardiac hypertrophy and fibrosis, suggesting that GC-A protects the heart from abnormal remodeling. We investigated whether GC-A interacts with AT1A signaling in the heart by target deletion and pharmacological blockade or stimulation of AT1A in mice.. We generated double-knockout (KO) mice for GC-A and AT1A by crossing GC-A-KO mice and AT1A-KO mice and blocked AT1 with a selective antagonist, CS-866. The cardiac hypertrophy and fibrosis of GC-A-KO mice were greatly improved by deletion or pharmacological blockade of AT1A. Overexpression of mRNAs encoding atrial natriuretic peptide, brain natriuretic peptide, collagens I and III, transforming growth factors beta1 and beta3, were also strongly inhibited. Furthermore, stimulation of AT1A by exogenous Ang II at a subpressor dose significantly exacerbated cardiac hypertrophy and dramatically augmented interstitial fibrosis in GC-A-KO mice but not in wild-type animals.. These results suggest that cardiac hypertrophy and fibrosis of GC-A-deficient mice are partially ascribed to an augmented cardiac AT1A signaling and that GC-A inhibits AT1A signaling-mediated excessive remodeling.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensinogen; Animals; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiomegaly; Collagen; Fibrosis; Gene Targeting; Guanylate Cyclase; Heart Rate; Heart Ventricles; Hypertension; Imidazoles; Mice; Mice, Knockout; Myocardium; Natriuretic Peptide, Brain; Olmesartan Medoxomil; Organ Size; Peptidyl-Dipeptidase A; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factor beta2; Ventricular Remodeling

1. Pre-eclampsia is a human disease of pregnancy characterized by high blood pressure, proteinuria and end-organ damage, if severe. Pre-eclampsia is thought to be related to changes in early placental development, with the formation of a shallower than normal placental bed. 2. Transforming growth factor (TGF)-beta1 is a multifunctional fibrogenic growth factor involved in immune regulation that is elevated in some populations with a high risk of hypertensive end-organ disease related to increases in endothelin release. Transforming growth factor-beta1 is also an important factor in placental implantation. Alterations in TGF-beta1 may be related to abnormal placental development in early pregnancy and, thus, are a candidate for the development of hypertension in pre-eclampsia. 3. The aim of the present study was to examine the placental distribution and serum concentration of TGF-beta1 in patients with pre-eclampsia compared with normal pregnancy. 4. Patients with pre-eclampsia (n = 12) were compared with patients with normal pregnancy (n = 14). Transforming growth factor-beta1 was determined by TGF-beta1 Max ELISA (Promega, Madsion, WI, USA) after serum dilution (1/150) and acid activation. Placental distribution was determined by immunostaining with TGF-beta1 (Santa Cruz, Santa Cruz, CA, USA; 20 ng/mL) and the villi and decidual trophoblast were scored for intensity and extent of staining. 5. Patients with pre-eclampsia had a mean gestational age of 36 weeks, whereas those with a normal pregnancy had a mean gestational age of 39.0 +/- 0.4 weeks. There was no difference in TGF-beta1 concentration between the two groups (mean (+/-SEM) 27.1 +/- 1.0 vs 26.4 +/- 0.7 pg/mL for normal pregnancy and pre-eclampsia, respectively; P = 0.73, Mann-Whitney U-test). There was no correlation between systolic or diastolic blood pressure and TGF-beta1 concentration (regression analysis P = 0.4 and 0.2). Immunostaining was absent in the villous trophoblast cells and endovascular and extravillous trophoblast of term placentas. 6. Although TGF-beta1 is present in trophoblast cells in early pregnancy during placental development, TGF-beta1 concentrations were not increased in the placenta at term in pre-eclampsia and there was no correlation between blood pressure and serum TGF-beta1, suggesting that TGF-beta1 does not play a role in the development of late gestation pre-eclampsia and hypertension.

Topics: Adult; Chi-Square Distribution; Female; Humans; Hypertension; Placenta; Pre-Eclampsia; Pregnancy; Statistics, Nonparametric; Transforming Growth Factor beta; Transforming Growth Factor beta1

To determine whether neuropeptide Y (NPY)-related mechanisms become activated with progression of cardiac hypertrophy in vivo, protein mass and de novo protein synthesis (incorporation of [(14)C]Phe, 0.1 muCi ml(-1)) were assessed in cardiomyocytes, obtained from spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats (8, 12, 16, 20, and 24 weeks of age), and cultured for 24 h. NPY (10(-8) M) increased protein mass of cardiomyocytes from 16-week-old SHRs by 9.2 +/- 2.1% (n = 8, P < 0.05). De novo protein synthesis was increased maximally in SHRs at 12, 16, and 20 weeks (P < 0.05, n = 8) in response to NPY by 12.6 +/- 2.1% (10(-6) M), 20.1 +/- 4.2% (10(-8) M), and 9.4 +/- 1.8% (10(-7) M), respectively. Peptide YY(3-36), (PYY(3-36)), which displays selectivity for NPY Y(2) and NPY Y(5) receptors, and the NPY Y(5)-selective agonist [D-Trp(34)]-NPY increased de novo protein synthesis maximally by 16.2 +/- 5.1% (10(-7) M; n = 4, P < 0.05) and 17.8 +/- 5.2% (10(-6) M; n = 7, P < 0.05), respectively, in SHRs at 16 weeks, whereas [Leu(31)Pro(34)]-NPY (< or =10(-6) M), which displays some activity at NPY Y(1) and NPY Y(4) receptors, did not. The NPY Y(1)-selective antagonist BVD-42 (2 x 10(-7) M) and the NPY Y(2)-selective antagonist BIIE0246 (2 x 10(-7) M) did not attenuate responses to NPY (10(-7) M) and PPY(3-36) (10(-7) M). These data indicate that hypertrophic responsiveness to NPY, mediated via NPY Y(5) receptors, is induced transiently in SHR cardiomyocytes subsequent to onset of cardiomyocyte hypertrophy in response to pressure overload.

Topics: Animals; Cardiomegaly; DNA; Female; Heart; Humans; Hypertension; Male; Muscle Proteins; Myocardium; Neuropeptide Y; Phenylalanine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Time Factors; Transforming Growth Factor beta

We evaluated the cardioprotective effects of long-term treatment with celiprolol (for 5 weeks), a specific beta(1)-adrenoceptor antagonist with a weak beta(2)-adrenoceptor agonist action, on endothelin-1 and transforming growth factor (TGF)-beta(1) expression and cardiovascular remodeling in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Upregulated preproendothelin-1, endothelin ET(A) receptor, TGF-beta(1), c-fos, and type I collagen expression and extracellular signal-regulated kinase activities were suppressed by celiprolol. Celiprolol effectively inhibited vascular lesion formation such as medial thickness and perivascular fibrosis. These observations suggested that extracellular signal-regulated kinase and c-fos gene pathway may contribute to the cardiovascular remodeling of DOCA rats, and that cardioprotective effects of celiprolol on cardiovascular remodeling may be mediated, at least in part, by suppressed expression of endothelin-1 and TGF-beta(1).

Topics: Adrenergic beta-Antagonists; Animals; Blotting, Western; Body Weight; Celiprolol; Desoxycorticosterone; Endothelin-1; Gene Expression Regulation; Heart Ventricles; Hemodynamics; Hypertension; Male; Mitogen-Activated Protein Kinases; Organ Size; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Remodeling

Recent studies suggest that 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors (statins) exert their protective effects against cardiovascular diseases independently of their cholesterol-decreasing effects.. To clarify the effect of a statin on hypertensive nephrosclerosis.. We treated stroke-prone spontaneously hypertensive rats (spSHRs) chronically, starting at the age of 4 weeks, with cerivastatin (2 mg/kg per day by gavage) or vehicle. Physiological parameters, plasma chemistry and urine protein excretion were analysed. At 14 weeks of age, the rats had their kidneys removed for use in assays.. Compared with vehicle treatment, statin treatment reduced proteinuria and renal injury independently of blood pressure and cholesterol concentrations in spSHRs. Although expression of adhesion molecules and infiltration of inflammatory cells were not different whether or not cerivastatin treatment was used, renal fibrosis was significantly reduced in statin-treated spSHRs. We also found that expression of transforming growth factor-beta1 in kidneys was significantly inhibited in statin-treated spSHRs.. Cerivastatin prevents or retards hypertension-induced renal injury via inhibition of renal fibrosis and proteinuria. These results show the potential of statins as protective tools against proteinuric renal diseases, independent of their cholesterol-decreasing effects.

Topics: Animals; Blood Pressure; Genetic Predisposition to Disease; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Inflammation; Kidney; Lipids; Male; Nephrosclerosis; Proteinuria; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor (TGF)-beta activity is involved in several cardiovascular diseases owing to its effects on the growth of vascular smooth muscle cells and induction of extracellular matrix formation. We evaluated expression of TGF-beta in cardiovascular organs from stroke-prone spontaneously hypertensive rats (SHR-SP) which show severe cardiovascular damages with the development of hypertension. Twelve-week-old Wistar-Kyoto (WKY)/Izm rats and SHR-SP/Izm were loaded with 1% salt for 4 weeks. Aorta, heart and kidney were removed and evaluated histologically by hematoxylin-eosin staining. Expression of TGF-beta1 mRNA was evaluated by reverse transcription and polymerase chain reaction analysis in mRNA extracted with oligo dT-cellulose. Expression of TGF-beta1 protein was evaluated by Western blot analysis and immunohistochemical study in renal cortex. Whereas expression of TGF-beta1 mRNA was detected only in the heart of SHR-SP before salt loading, it was detected in the aorta, left ventricle of heart and renal cortex from both rat strains, and it was stronger in the renal cortex of SHR-SP than in the renal cortex of WKY rats. Expression of TGF-beta1 protein was markedly higher in the renal cortex of SHR-SP than in the renal cortex of WKY rats after salt loading. TGF-beta was localized at glomeruli and capillary arteries in the renal cortex, and immunostaining was stronger in SHR-SP than in WKY rats. Expression of TGF-beta1 was increased in glomeruli and capillaries of the renal cortex with the development of hypertension in SHR-SP. These results implicate TGF-beta in the renal damage observed in hypertension.

Topics: Animals; Blood Pressure; Cardiovascular System; Genetic Predisposition to Disease; Hypertension; Immunohistochemistry; Kidney Cortex; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Stroke; Transforming Growth Factor beta

The effects and mechanism of long-term angiotensin converting enzyme inhibitor (ACEI) Forsinopril on left ventricular hypertrophy of spontaneous hypertension rat (SHR) and left ventricular pressure overloading rat were studied. The left ventricular index (left ventricle weight/body weight) was used to evaluate left ventricular hypertrophy and the in situ hybridization to investigate the TGF-beta 1 gene expression in left ventricle. The results showed that Forsinopril significantly decreased the left ventricular index of both SHR and left ventricle pressure overloading rat. Forsinopril reduced the integral photic density of TGF-beta 1 gene statement from 2.836 +/- 0.314 to 1.91 +/- 0.217 (P < 0.01, n = 8) of SHR rat and from 3.071 +/- 0.456 to 2.376 +/- 0.379 (P < 0.01, n = 8) of left ventricular pressure overloading rat respectively. It was concluded that Forsinopril could prevent the occurrence of left ventricular hypertrophy and reduce the TGF-beta 1 gene expression in left ventricle of both SHR and left ventricular pressure overloading rat significantly.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Female; Fosinopril; Hypertension; Hypertrophy, Left Ventricular; Male; Myocardium; Random Allocation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Transforming Growth Factor beta

Increased intraglomerular pressure is considered a major factor for increased albumin excretion in hypertension. However, other factors should also be considered because recent studies in both humans and rats have demonstrated that proteins undergoing filtration and renal passage are extensively modified by renal cell lysosomal processing; >95% of albumin is degraded to peptides that are not detected by routine immunochemical assays. Changes in postglomerular lysosomal processing may therefore be responsible for the increased intact albumin excreted in hypertension-related kidney disease. We hypothesize that transforming growth factor-beta, which is known to decrease lysosomal activity, may be upregulated in hypertension and may play a role in increased intact albumin excretion. The aims of this study were to determine the effect that hypertension has on (1) renal cell lysosomal processing of albumin and dextran sulfate, (2) glomerular permeability, and (3) renal transforming growth factor-beta(1) expression. Spontaneously hypertensive rats and Wistar-Kyoto rats were used at 8, 16, and 24 weeks. We demonstrate that albuminuria in hypertension is linked to an inhibition of lysosomal processing as determined by (1) size exclusion chromatography analysis of urinary [(14)C]albumin structural integrity and (2) ion exchange analysis of urinary [(3)H]dextran sulfate. This inhibition gives rise to an increased proportion of radioimmunoassay detectable (intact) albumin and intact dextran sulfate independent of changes in glomerular capillary wall permeability as determined by the fractional clearance of [(3)H]Ficolls of various radii. These changes may be correlated with increased renal transforming growth factor-beta(1) expression.

Topics: Albuminuria; Animals; Blood Pressure; Extracellular Matrix Proteins; Gene Expression; Glomerular Filtration Rate; Hypertension; Kidney; Lysosomes; Male; Neoplasm Proteins; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Sulfatases; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that has been linked to vascular remodeling processes, myocardial hypertrophy, and renal fibrosis. Recently a correlation between serum levels of TGF-beta1 and blood pressure (BP) levels in patients with end-stage renal disease was shown. In addition, it is not clear whether TGF-beta1 is a causative factor in the pathogenesis of essential hypertension and associated with hypertensive target organ damage (TOD).. Using a TGF-beta1-specific sandwich ELISA, we compared plasma levels of active and total TGF-beta1 of 30 normotensive persons and 85 patients with essential hypertension with and without TOD, as measured by microalbuminuria or left ventricular hypertrophy.. Active and total TGF-beta1 levels were significantly higher in plasma of patients with essential hypertension than in normotensive controls (P < .05 and P < .01, respectively). However, neither active nor total TGF-beta1 correlated with systolic or diastolic BP (R2 < 0.14 for all parameters). Levels of active and total TGF-beta1 were significantly higher in hypertensive patients with than without TOD (P < .05).. Active and latent TGF-beta1 levels are markedly increased in plasma of hypertensive patients. We assume that TGF-beta1 contributes substantially to the development of TOD in essential hypertension, independent of BP levels.

Topics: Blood Pressure; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Transforming Growth Factor beta; Transforming Growth Factor beta1

With a view to evaluating the putative involvement of cytokine gene variants in human essential hypertension, we carried out an association (case-control) study on 174 unrelated nationals (81 hypertensives and 93 normotensives) from the Abu Dhabi Emirate (UAE), a genetically homogeneous population also characterised by the absence of traditional confounding factors such as alcohol consumption and smoking. To that end, we targeted our investigation to five candidate gene loci-transforming growth factor beta1 (TGF-beta1), interferon gamma (IFN-gamma), epidermal growth factor (EGF), interleukin-1 beta (IL-1beta) and tumour-necrosis factor (TNF-alpha) genes. We investigated the distribution of genotypes and alleles of the six following dimorphic variants: TGF-beta1(*)10(T>C) and TGF-beta1(*)25(G>C), located at codons 10 and 25, respectively, of TGF-beta1; T874A in intron 1 of IFN-gamma; G61A in exon 1 of EGF; TaqI dimorphism at +3962 (exon 5) of IL-1beta; and -308A>G in the promoter of TNF-alpha. These six bi-allelic markers were visualised by methods based on the techniques of amplification refractory mutation system-polymerase chain reaction (for TGF-beta1, IFN-gamma, EGF and TNF-alpha) and by polymerase chain reaction-TaqI restriction endonuclease analysis in the case of IL-1beta. In each of the two groups (normotensives and hypertensives), genotype frequencies of all six markers occurred in Hardy-Weinberg proportions. There were, however, no statistical differences in the allele and genotype frequencies of any of the six markers between the two groups of subjects: TGF-beta1(*)10C frequencies were 0.46 and 0.49 (chi(2)=0.61; 2 d.f.; P=0.74) and TGF-beta1(*)25C were 0.07 and 0.08 (chi(2)=0.61; 2 d.f.; P=0.74) amongst normotensives and hypertensives, respectively; p(IFN-gamma(*)A874) were 0.41 in normotensives versus 0.46 in hypertensives (chi(2)=3.07; 2 d.f.; P=0.22); p(EGF (*)G61) were 0.51 versus 0.58 (chi(2)=1.76; 2 d.f.; P=0.41); p[IL-1beta (*)TaqI(+)] were 0.43 versus 0.36 (chi(2)=2.08; 2 d.f.; P=0.35); and p(TNF-alpha(*)-308G) were 0.80 versus 0.85 (chi(2)=1.29; 2 d.f.; P=0.53). There was also no difference in distribution and frequencies of haplotypes constructed with combinations of TGF-beta1(*)10(T>C) and TGF-beta1(*)25(G>C) sites. However, although they do not reach statistical significance (which may be due to the relatively restricted number of subjects included in this study), the distribution differences (in normotensives and hypertensives) ob

Topics: Case-Control Studies; Cytokines; Epidermal Growth Factor; Female; Gene Frequency; Genes; Genotype; Humans; Hypertension; Interferon-gamma; Interleukin-1; Male; Middle Aged; Pilot Projects; Retrospective Studies; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha; United Arab Emirates

Transforming growth factor-beta1 (TGF-beta1) is an important regulator of blood pressure (BP) and vascular remodeling, and thus may contribute to the pathogenesis of hypertension. A T-->C transition at nucleotide 869 of the TGF-beta1 gene results in a Leu-->Pro substitution at amino acid 10 of the signal peptide. We have now examined the possible association of the 869T-->C polymorphism of the TGF-beta1 gene with BP and the prevalence of hypertension in 2241 community-dwelling Japanese individuals (1126 men and 1115 women). TGF-beta1 genotype was determined by an allele-specific polymerase chain reaction method. For women, both systolic and diastolic BP was significantly higher in individuals with the CC genotype than in those with the TT or TC genotype. No significant association between TGF-beta1 genotype and BP was detected in men. The frequency of the CC genotype was significantly higher in women with hypertension than in those with normal BP. These results suggest that the TGF-beta1 gene at chromosome 19q13.1 may be a candidate susceptibility locus for hypertension in Japanese women.

Topics: Adult; Aged; Aging; Blood Pressure; Cohort Studies; DNA Primers; Female; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Prospective Studies; Transforming Growth Factor beta

We evaluated the protective effects of long-term treatment with betaxolol, a specific beta-antagonist, on platelet-derived growth factor (PDGF) A-chain and transforming growth factor (TGF)-beta1 gene expression in the left ventricle of Dahl salt-sensitive hypertensive rats fed a high-salt diet. In addition, we evaluated the relations between these effects and coronary microvascular remodeling, expression of extracellular signal-regulated kinases (ERK) belonging to one subfamily of mitogen-activated protein kinases, and expression of p70S6 kinase belonging to one subfamily of ribosomal S6 kinases. Betaxolol (0.9 mg/kg/day, subdepressor dose) was administered for 5 weeks, from 6 weeks of age to the left ventricular hypertrophy stage at 11 weeks of age. Increased PDGF A-chain and TGF-beta1 mRNA and protein expression were suppressed by betaxolol. Upregulated activities of ERK1/2 and p70S6 kinase phosphorylations were decreased by betaxolol. Betaxolol administration resulted in significant improvements in the wall-to-lumen ratio, perivascular fibrosis and myocardial fibrosis. Thus, we conclude that ERK1/2 and p70S6 kinase activities may play a key role in coronary microvascular remodeling of Dahl salt-sensitive hypertensive rats, and that beneficial effects of betaxolol on cardiovascular remodeling may be at least partially mediated by decreased PDGF A-chain and TGF-beta1 expression in the left ventricle.

Topics: Adrenergic beta-Antagonists; Animals; Betaxolol; Body Weight; Gene Expression; Hemodynamics; Hypertension; Male; Mitogen-Activated Protein Kinases; Myocardium; Organ Size; Phosphorylation; Platelet-Derived Growth Factor; Rats; Rats, Inbred Dahl; Ribosomal Protein S6 Kinases, 70-kDa; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

The present study was designed to examine whether chronic adrenomedullin infusion has renoprotective effects in hypertensive renal failure and the mechanism by which chronic adrenomedullin infusion exerts its effects. Dahl salt-sensitive rats and Dahl salt-resistant rats were fed a high salt diet starting at 6 weeks of age. Recombinant human adrenomedullin or vehicle was infused for 7 weeks in 11-week-old Dahl salt-sensitive rats. Dahl salt-resistant rat was used as a control. After 7 weeks, untreated Dahl salt-sensitive rats were characterized by decreased kidney function, abnormal morphological findings, increased hormone levels, increased renal tissue angiotensin II levels, and altered mRNA expressions of transforming growth factor beta (TGF-beta) and components of the renin-angiotensin system compared with Dahl salt-resistant rats. Chronic adrenomedullin treatment significantly improved renal function (serum creatinine -87%, creatinine clearance +114%, urinary protein excretion -59%) and histological findings (glomerular injury score -54%) without changing mean arterial pressure compared with untreated Dahl salt-sensitive rats. Interestingly, long-term human adrenomedullin infusion decreased the endogenous rat adrenomedullin level (-97%) with a slight increase of human adrenomedullin level. Chronic adrenomedullin treatment also significantly inhibited the increase of plasma renin concentration (-269%), aldosterone level (-82%), and renal tissue angiotensin II levels (-60%). Furthermore, adrenomedullin infusion significantly decreased the increases of mRNA expressions of TGF-beta (- 63%), angiotensin-converting enzyme (-137%), renin (-230%), and angiotensinogen (-38%) in renal cortex. These results suggest that increased endogenous adrenomedullin plays a compensatory role in chronic hypertensive renal failure and that long-term adrenomedullin infusion has renoprotective effects in this type of hypertension model, partly via inhibition of the circulating and renal renin-angiotensin system.

Topics: Adrenomedullin; Angiotensin II; Animals; Creatinine; Drug Implants; Glomerulonephritis; Hormones; Hypertension; Kidney; Male; Peptides; Proteinuria; Rats; Rats, Inbred Dahl; Renal Insufficiency; Renin-Angiotensin System; RNA, Messenger; Sodium Chloride; Time Factors; Transforming Growth Factor beta

Recent studies have indicated that a number of factors contribute to the pathophysiology in response to nitric oxide synthase (NOS) inhibition. We previously demonstrated that plasminogen activator inhibitor-1 deficient (PAI-1-/-) mice are protected against hypertension and perivascular fibrosis induced by relatively short-term NOS inhibition. In this study, we compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis induced by long-term treatment with N(omega)-nitro- L -arginine methyl ester (L -NAME) in wild type (WT), PAI-1(-/-) and tissue-type plasminogen activator deficient (t-PA-/-) mice. After initiating L -NAME, systolic blood pressure increased in all groups at 2 weeks. Over a 16 week study period, systolic blood pressure increased to 143+/-3 mmHg (mean+/-SEM) in WT animals, 139+/-2 in t-PA-/- mice vs 129+/-2 in PAI-1-/- mice (P < 0.01). Coronary perivascular fibrosis increased in L -NAME-treated WT and t-PA(-/-) mice compared to each control group (P<0.01 in WT, P<0.05 in t-PA-/-), while PAI-1-/- mice were protected against fibrosis induced by L -NAME. t-PA deficiency did not accentuate the vascular pathology or the changes in blood pressure. In situ zymography demonstrated augmented gelatinolytic activity in PAI-1-/- mice at baseline, suggesting that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation. Plasma TGF-beta1 levels increased in L -NAME-treated WT and PAI-1-/- mice (P < 0.01), but not in L -NAME-treated t-PA-/- mice. These findings support the hypothesis that the plasminogen activator system protects against the structural vascular changes induced by long-term NOS inhibition. While PAI-1 deficiency protects against L -NAME-induced hypertension and perivascular fibrosis, t-PA deficiency does not exacerbate the vascular pathology or hypertension.

Topics: Animals; Body Weight; Coronary Disease; Coronary Vessels; Enzyme Inhibitors; Fibrosis; Hemodynamics; Hypertension; Mice; Mice, Inbred C57BL; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Plasminogen Activators; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta

Excessive myocardial fibrosis impairs cardiac function in hypertensive hearts. Roles of transforming growth factor (TGF)-beta in myocardial remodeling and cardiac dysfunction were examined in pressure-overloaded rats.. Pressure overload was induced by a suprarenal aortic constriction in Wistar rats. Fibroblast activation (proliferation and phenotype transition to myofibroblasts) was observed after day 3 and peaked at days 3 to 7. Thereafter, myocyte hypertrophy and myocardial fibrosis developed by day 28. At day 28, echocardiography showed normal left ventricular fractional shortening, but the decreased ratio of early to late filling velocity of the transmitral Doppler velocity and hemodynamic measurement revealed left ventricular end-diastolic pressure elevation, indicating normal systolic but abnormal diastolic function. Myocardial TGF-beta mRNA expression was induced after day 3, peaked at day 7, and remained modestly increased at day 28. An anti-TGF-beta neutralizing antibody, which was administered intraperitoneally daily from 1 day before operation, inhibited fibroblast activation and subsequently prevented collagen mRNA induction and myocardial fibrosis, but not myocyte hypertrophy. Neutralizing antibody reversed diastolic dysfunction without affecting blood pressure and systolic function.. TGF-beta plays a causal role in myocardial fibrosis and diastolic dysfunction through fibroblast activation in pressure-overloaded hearts. Our findings may provide an insight into a new therapeutic strategy to prevent myocardial fibrosis and diastolic dysfunction in pressure-overloaded hearts.

Topics: Animals; Antibodies; Cardiomegaly; Diastole; Fibroblasts; Fibrosis; Hemodynamics; Hypertension; Kinetics; Male; Myocardium; Pressure; Rats; Rats, Wistar; RNA, Messenger; Transforming Growth Factor beta; Ventricular Dysfunction, Left

To test the hypothesis that endothelin-1 contributes to cardiac fibrosis, cardiac collagen deposition was studied in deoxycorticosterone acetate-salt (DOCA-salt) hypertensive rats, in which the endothelin system is activated. The effects of the ET(A)-selective endothelin receptor antagonist A-127722 were evaluated.. A-127722 (30 mg/kg per day) was administered for 4 weeks. Myocardial fibrosis was evaluated after Sirius red F3BA staining. Systolic blood pressure was 103+/-1.6 mm Hg in unilaterally nephrectomized rats (Uni-Nx), 202+/-3.2 mm Hg in DOCA-salt rats (P:<0.01 versus Uni-Nx), and 182+/-3.1 mm Hg in ET(A) antagonist-treated DOCA-salt rats (P:<0.01 versus DOCA-salt or Uni-Nx). In DOCA-salt rats, interstitial and perivascular collagen density was increased in the subendocardial and midmyocardial regions of the left ventricle (3- to 4-fold, P:<0.05), whereas in subepicardial myocardium, the increase was predominantly perivascular. The ET(A) antagonist prevented cardiac fibrosis in DOCA-salt rats. Procollagen I and III mRNA, which were increased in hearts of DOCA-salt rats, were normalized by ET(A) antagonist treatment. TGF-beta(1) mRNA and TGF-beta(1) protein increased at 1 week in DOCA-salt rats and were lowered in ET(A) antagonist-treated rats.. ET(A) receptor-mediated collagen deposition in hearts of DOCA-salt rats results from increased procollagen synthesis associated with an initial increment in expression of TGF-beta(1). These results support the hypothesis of a role for endothelin-1 in cardiac collagen deposition in mineralocorticoid hypertension, which may have pathophysiological and pharmacological implications in hypertensive heart disease.

Topics: Animals; Atrasentan; Blood Pressure; Collagen; Collagen Type I; Desoxycorticosterone; Endothelin A Receptor Antagonists; Fibrosis; Hypertension; Male; Myocardium; Organ Size; Pyrrolidines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sodium Chloride; Transforming Growth Factor beta; Transforming Growth Factor beta1

The molecular basis of vascular response to hypertension is largely unknown. Both cellular and extracellular components are critical. In the current study we tested the hypothesis that there is a balance between vascular cell proliferation and cell death during vessel remodeling in response to hypertension.. A midthoracic aortic coarctation was created in rats to induce an elevation of blood pressure proximal to the coarctation. The time course was 1 and 3 days and 1, 2, and 4 weeks for the study of the proximal aorta. Ribonuclease protection assay and Western blot analysis were used to evaluate gene expression of growth and apoptosis-related cytokines with two sets of multiple probes, rCK-3 and rAPO-1. Cell proliferation was determined with BrdU (5-bromo-2'-deoxyuridine) incorporation. Apoptosis was examined with TUNEL (transferase-mediated dUTP nick end-labeling). Morphometry was performed on histologic sections.. Coarctation produced hypertension in the proximal aorta, 118 +/- 9 mm Hg versus 94 +/- 6 mm Hg in controls (P <.002). Both messenger RNA and protein levels of transforming growth factor (TGF)-beta1 and TGF-beta3 were increased (P <.005 vs controls). Messenger RNA and protein of Bcl-xS and Fas ligand, known as proapoptotic factors, were both reduced after coarctation (P <.005 vs controls). There was increased BrdU incorporation at 3 days and 1 and 2 weeks (P <.001 vs controls). There were no remarkable changes in the apoptosis rate until 4 weeks later.. Cell proliferation was stimulated at 3 days, and apoptosis was halted until 4 weeks. These changes were associated with upregulation of TGF-beta and downregulation of Bcl-xS and Fas ligand gene expression. These findings suggest that a coordinated regulation of cell proliferation and cell death contributes to arterial remodeling in response to acute sustained elevation of blood pressure. Cell proliferation precedes apoptosis by 2 weeks in this procedure.

Topics: Animals; Aortic Coarctation; bcl-X Protein; Cell Death; Cell Division; Down-Regulation; Fas Ligand Protein; Gene Expression; Hypertension; Membrane Glycoproteins; Muscle, Smooth, Vascular; Proto-Oncogene Proteins c-bcl-2; Rats; RNA, Messenger; Transforming Growth Factor beta; Up-Regulation

Angiotensin II plays a pivotal role in the development of diabetic nephropathy, but it remains controversial as to the best approach to effectively block the actions of this hormone in the kidney. The aim of the present study was to explore the effects of long-term treatment (8 months) with a combination of an angiotensin type 1 (AT1) receptor antagonist, irbesartan (15 mg/kg per day), and an angiotensin-converting enzyme (ACE) inhibitor, captopril (100 mg/kg per day), in diabetic spontaneously hypertensive rats. Captopril treatment reduced blood pressure (163+/-3 mmHg versus diabetic 201+/-3 mmHg), but not albumin excretion rate (43.8x//1.3 mg/day versus diabetic 46.8x//1.4 mg/day). Irbesartan treatment was associated with a similar reduction in blood pressure (173+/-3 mmHg) to captopril, and albumin excretion rate was reduced (14x//1.5 mg/day). The combination of irbesartan and captopril induced further reductions in blood pressure (140+/-3 mmHg) and albumin excretion rates (4.0x//1.5 mg/day). Gene expression of transforming growth factor beta-1 was reduced by all treatments to a similar level as assessed by in situ hybridization. These results demonstrate the additive hypotensive and anti-albuminuric effects of an ACE inhibitor and an AT1 receptor, suggesting that combination therapy is an approach not only more effective at reducing blood pressure, but also at retarding the development of diabetic nephropathy.

Topics: Albuminuria; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Captopril; Drug Therapy, Combination; Gene Expression; Hypertension; Irbesartan; Kidney; Rats; Rats, Inbred SHR; Renin; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Transforming Growth Factor beta1

To assess if the renal damage observed in rats with diabetes and hypertension is due to hemodynamic or metabolic changes, a progressive aortic constriction between the two renal arteries has been done in streptozotocin-induced diabetic rats (constriction + diabetes group) and in nondiabetic rats (constriction group). This model allows us to study two kidneys subjected to different perfusion pressure (PP) in the same metabolic environment. One-month-old rats (100-120 g body wt) were subjected to the aortic constriction procedure. Three months after constriction, glomerular filtration rate and renal plasma flow were similar in both kidneys of the two groups. PP was greater in the kidney placed over the ligature [constriction high-pressure kidney (CH) or constriction + diabetic high-pressure kidney (DH)] than in the one placed below the ligature [constriction low pressure (CL) or constriction + diabetic low pressure (DL)]. Proteinuria was higher in the CH than in the CL kidneys (512 +/- 61 vs. 361 +/- 38 microg/30 min, respectively) and much higher in the DH kidney (770 +/- 106 microg/30 min). Renal fibrosis was measured in tissue sections stained with Syrius red using a computer-assisted image analysis system. DH and DL kidneys showed higher corpuscular cross-sectional and capillary tuft areas than the CH and CL ones. The DH kidney showed slight mesangial expansion and thickening of the capillary walls, which were more pronounced in the former. Most renal corpuscles from CH and DH groups were nearly normal in morphology appearance, and only in some instances a slight increment in mesangium was observed. Transforming growth factor-beta1 (TGF-beta1) immunostaining revealed that DH kidneys showed the highest glomerular expression. We concluded that 1) diabetic animals develop glomerular but not interstitial fibrosis to a greater extent than nondiabetic animals and that this lesion principally occurs in the hypertensive kidney (DH), and 2) increased TGF-beta expression is associated with diabetic renal damage.

Topics: Animals; Aorta; Blood Pressure; Carotid Arteries; Constriction; Diabetes Mellitus, Experimental; Diuresis; Femoral Artery; Fibrosis; Glomerular Filtration Rate; Hypertension; Kidney; Kidney Glomerulus; Male; Natriuresis; Potassium; Proteinuria; Rats; Rats, Wistar; Renal Circulation; Transforming Growth Factor beta; Transforming Growth Factor beta1

Endothelin and growth factors such as transforming growth factor (TGF)-beta1 are important regulators of the cardiovascular system. Although increased production of endothelin-1 (ET-1) and TGF-beta1 have been reported in left ventricular hypertrophy, the detailed roles of these substances in hypertrophy remain to be determined. To elucidate the cardioprotective effects of calcium antagonists in left ventricular hypertrophy, we evaluated the effects of long-term treatment with benidipine, a long-acting calcium antagonist, on preproET-1, ET(A) receptor (ETAR) and TGF-beta1 expression in the left ventricle and evaluated the relations between these effects and myocardial remodeling in Dahl salt-sensitive hypertensive (DS) rats fed a high-salt diet. After 5 weeks of feeding an 8% NaCl diet to 6-week-old DS rats (i.e., at 11 weeks of age), a distinct stage of concentric left ventricular hypertrophy (DSLVH) was noted. Benidipine (DSLVH-B group, n= 8; 1 mg/kg/day, subdepressor dose) or vehicle (DSLVH-V group, n=8) was administered to 6-week-old DS rats for 5 weeks, or until the onset of DSLVH stage, and age-matched (11-week-old) Dahl salt-resistant rats fed the same diet served as a control group (DR-C, n=8). Blood pressure was similar between the DSLVH-B and DSLVH-V groups, but was significantly lower in DR-C rats. The preproET-1, ETAR and TGF-beta1 expressions in the left ventricle were significantly higher in DSLVH-V than in DR-C rats, and significantly lower in DSLVH-B than in DSLVH-V. Benidipine administration resulted in significant improvements in the wall-to-lumen ratio and perivascular fibrosis in the coronary arterioles, and in myocardial fibrosis. We therefore concluded that myocardial remodeling and left ventricular hypertrophy in DS hypertensive rats fed a high-salt diet were significantly ameliorated by a subdepressor dose of benidipine, and that this amelioration was partly due to decreases in the expression of ET-1 and TGF-beta1 in the left ventricle.

Topics: Animals; Blood Pressure; Blotting, Western; Calcium Channel Blockers; Dihydropyridines; Endothelin-1; Endothelins; Gene Expression; Heart Ventricles; Hypertension; Male; Myocardium; Organ Size; Protein Precursors; Rats; Rats, Inbred Dahl; Receptor, Endothelin A; Receptors, Endothelin; RNA, Messenger; Sodium Chloride, Dietary; Transforming Growth Factor beta; Transforming Growth Factor beta1; Ventricular Remodeling

The roles of angiotensin II (Ang II) in the regulation of heart function under normal and pathological conditions have been well documented. Although 2 types of Ang II receptor (AT(1) and AT(2)) are found in various proportions, most studies have focused on AT(1)-coupled events. In the present study, we examined the hypothesis that signaling by AT(2) is important to the development of left ventricular hypertrophy and cardiac fibrosis by Ang II infusion in mice lacking the AT(2) gene (Agtr2-/Y).. Male Agtr2-/Y and age-matched wild-type (WT) mice were treated long-term with Ang II, infused at a rate of 4.2 ng. kg(-1). min(-1) for 3 weeks. Ang II elevated systolic blood pressure to comparable levels in Agtr2-/Y and WT mice. WT mice developed prominent concentric cardiac hypertrophy, prominent fibrosis, and impaired diastolic relaxation after Ang II infusion. In contrast, there was no cardiac hypertrophy in Agtr2-/Y mice. Agtr2-/Y mice, however, did not show signs of heart failure or impairment of ventricular relaxation and only negligible fibrosis after Ang II infusion. The absence of fibrosis may be a clue to the absence of impairment in ventricular relaxation and account for the normal left ventricular systolic and diastolic performances in Agtr2-/Y mice.. Chronic loss of AT(2) by gene targeting abolished left ventricular hypertrophy and cardiac fibrosis in mice with Ang II-induced hypertension.

Topics: Angiotensin II; Animals; Chronic Disease; Collagen; Diastole; Disease Models, Animal; Echocardiography; Echocardiography, Doppler; Endomyocardial Fibrosis; Fibronectins; Hypertension; Hypertrophy, Left Ventricular; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; RNA, Messenger; Systole; Transforming Growth Factor beta; Transforming Growth Factor beta1

1. The effect of carvedilol on renal function, structure and expression of TGF beta and the matrix proteins fibronectin, collagen I and collagen III, was evaluated in spontaneously hypertensive stroke-prone (SHR-SP) rats fed a high fat, high salt diet. 2. Carvedilol treatment for 11 to 18 weeks did not alter systolic blood pressure in SHR-SP rats, however, it resulted in a significant reduction in heart rate. 3. Carvedilol treatment reduced renal fibrosis and total, active and chronic renal damage to levels approaching those of WKY rats on a normal diet. 4. Urinary protein excretion was higher in SHR-SP rats (51+/-10 mg day(-1)) than WKY rats (18+/-2 mg day(-1)) and this was further increased when SHR-SP rats were fed a high fat, high salt diet (251+/-120 mg day(-1)). Treatment with carvedilol resulted in significantly lower urinary protein excretion (37+/-15 mg day(-1)). 5. The expression of TGF beta mRNA was significantly higher in SHR-SP rats compared to WKY rats and a further increase was observed when rats were fed a high fat, high salt diet. Renal TGF beta expression was significantly reduced by treatment with carvedilol. The expression of fibronectin and collagen I and collagen III mRNA showed a pattern similar to that observed with TGF beta mRNA expression. Collagen I mRNA expression followed a pattern similar to renal fibrosis. 6. These data indicate that carvedilol can provide significant renal protection in the absence of any antihypertensive activity and that the mechanisms involved in this action may include reduced expression of profibrotic factors such as TGF beta.

Topics: Adrenergic beta-Antagonists; Animals; Blood Pressure; Carbazoles; Carvedilol; Collagen Type I; Dietary Fats; Female; Fibronectins; Fibrosis; Gene Expression Regulation; Heart Rate; Hypertension; Kidney; Male; Propanolamines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Severity of Illness Index; Sodium Chloride, Dietary; Transforming Growth Factor beta

1. Calcium channel blockers (CCBs) are anti-hypertensive drugs that are usually considered to act mainly as vasodilators. We investigated the relation between the reduction of blood pressure evoked by two long-acting CCBs and their protective effect against cardiac and renal damage in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). 2. SHRSP were exposed to high dietary salt intake (1% NaCl in drinking solution) from 8 to 14 weeks of age, with or without amlodipine or lacidipine at three dosage regimens producing similar effects on blood pressure. 3. The lowest dosages of both drugs had non-significant effects on blood pressure but inhibited the paradoxical increases in plasma renin activity (PRA) and in renin mRNA in kidney that were found in salt-loaded SHRSP. The lowest dosage of lacidipine (but not of amlodipine) restored the physiological downregulation of renin production by high salt and reduced left ventricular hypertrophy and mRNA levels of atrial natriuretic factor and transforming growth factor-beta1. 4. The intermediate dosages reduced blood pressure and PRA in a comparable manner, but cardiac hypertrophy was more reduced by lacidipine than by amlodipine. 5. Although the highest doses exhibited a further action on blood pressure, they had no additional effect on cardiac hypertrophy, and they increased PRA and kidney levels of renin mRNA even more than in the absence of drug treatment. 6. We conclude that reduction of blood pressure is not the sole mechanism involved in the prevention of cardiac remodelling by CCBs, and that protection against kidney damage and excessive renin production by low and intermediate dosages of these drugs contributes to their beneficial cardiovascular effects.

Topics: Actins; Amlodipine; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium Channel Blockers; Collagen Type I; Dihydropyridines; Dose-Response Relationship, Drug; Fibrosis; Gene Expression Regulation; Heart Ventricles; Hypertension; Hypertrophy; Kidney; Male; Muscle, Skeletal; Rats; Rats, Inbred SHR; Renin; RNA, Messenger; Sodium Chloride, Dietary; Transforming Growth Factor beta; Transforming Growth Factor beta1

Hypertension, a remediable risk factor for stroke, cardiovascular disease, and renal failure, affects 50 million individuals in the United States alone. African Americans (blacks) have a higher incidence and prevalence of hypertension and hypertension-associated target organ damage compared with Caucasian Americans (whites). Herein, we explored the hypotheses that transforming growth factor-beta(1) (TGF-beta(1)) is hyperexpressed in hypertensives compared with normotensives and that TGF-beta(1) overexpression is more frequent in blacks compared with whites. These hypotheses were stimulated by our recent demonstration that TGF-beta(1) is hyperexpressed in blacks with end-stage renal disease compared with white end-stage renal disease patients and by the biological attributes of TGF-beta(1), which include induction of endothelin-1 expression, stimulation of renin release, and promotion of vascular and renal disease when TGF-beta(1) is produced in excess. TGF-beta(1) profiles were determined in black and white hypertensive subjects and normotensive controls and included circulating protein concentrations, mRNA steady-state levels, and codon 10 genotype. Our investigation demonstrated that TGF-beta(1) protein levels are highest in black hypertensives, and TGF-beta(1) protein as well as TGF-beta(1) mRNA levels are higher in hypertensives compared with normotensives. The proline allele at codon 10 (Pro(10)) was more frequent in blacks compared with whites, and its presence was associated with higher levels of TGF-beta(1) mRNA and protein. Our findings support the idea that TGF-beta(1) hyperexpression is a risk factor for hypertension and hypertensive complications and provides a mechanism for the excess burden of hypertension in blacks.

Topics: Base Sequence; Black or African American; Codon; DNA Primers; Genotype; Humans; Hypertension; RNA, Messenger; Transforming Growth Factor beta

Despite the documented association between apolipoprotein E genotype and cerebral amyloid angiopathy (CAA), a substantial proportion of CAA-related hemorrhages occur in patients without known risks for this disorder. Two other factors implicated in the pathogenesis of CAA are the amyloid-beta peptide (preferentially deposited in vessels as a 40-amino acid species) and the multifunctional cytokine transforming growth factor-beta 1 (a specific promoter of vascular amyloid deposition in transgenic models). We measured plasma concentrations of these factors in a series of 25 patients diagnosed with probable or definite CAA-related hemorrhage and compared them with 21 patients with hemorrhage due to probable hypertensive vasculopathy and 42 elderly control subjects without hemorrhage. We found no differences among the groups in concentrations of the 40- or 42-amino acid species of beta-amyloid or either the active or latent form of transforming growth factor-beta 1. While the data do not exclude important roles for these molecules as risks for CAA, they indicate that plasma measurements are not useful in its diagnosis.

Topics: Aged; Amyloid beta-Peptides; Biomarkers; Cerebral Amyloid Angiopathy; Cerebral Hemorrhage; Female; Humans; Hypertension; Male; Peptide Fragments; Reference Values; Risk Factors; Transforming Growth Factor beta

To investigate the role of transforming growth factor-beta1 (TGF-beta1) on Ca2+-dependent mechanisms elicited by angiotensin II in aortic vascular smooth muscle cells (VSMC) of Wistar- Kyoto (WKY) rats and spontaneously hypertensive rats (SHR).. Cai2+ release induced by angiotensin II (1 micromol/ l) was studied in cultured VSMC isolated from the aortas of 6-week-old WKY rats and SHR. Intracellular Ca2+ (Cai2+) was assessed in Fura-2 loaded cells using fluorescent imaging microscopy. Angiotensin II receptors were analysed by binding studies.. Pretreatment of VSMC for 24 h with TGF-beta1 significantly increased angiotensin II-induced Cai2+ mobilization from internal stores in SHR, while Ca2+ influx was not altered. This effect involves tyrosine kinase and is not due to an increase in angiotensin II binding sites, or a change in the affinity of the receptors. By contrast, TGF-beta1 did not modify the response of VSMC from WKY rats to angiotensin II.. These results help our understanding of the interactions between the pathways activated by TGF-beta1 and the G protein-coupled receptor signalling pathway, and their role in genetic hypertension.

Topics: Angiotensin II; Animals; Binding Sites; Biological Transport; Calcium; Cells, Cultured; Enzyme Inhibitors; Hypertension; Male; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; Thapsigargin; Transforming Growth Factor beta

Topics: Female; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic; Transforming Growth Factor beta; Transforming Growth Factor beta1

Oxidized low-density lipoprotein (OxLDL) has been implicated in atherosclerosis and glomerulosclerosis. LOX-1 is a recently identified OxLDL receptor that is abundantly expressed in vascular endothelial cells. The aim of the present study was to investigate LOX-1 expression in the kidneys of hypertensive rats. Dahl salt-sensitive (DS) and salt-resistant (DR) rats were fed a 0.3% or 8% NaCl diet. Some DS 8% rats were treated with manidipine or hydralazine. LOX-1 gene expression was markedly elevated in the kidneys and glomeruli of hypertensive DS 8% rats compared with those of normotensive DR and DS 0.3% rats. Prolonged salt loading further increased the renal LOX-1 expression in DS rats. The LOX-1 upregulation in DS 8% rats was accompanied by renal overexpression of transforming growth factor-beta 1 and type I collagen, impaired renal function, and histologic glomerulosclerotic changes, all of which were ameliorated by antihypertensive treatment. LOX-1 was indeed expressed in the glomeruli in vivo and in cultured glomerular cells in vitro. However, LOX-1 expression was elevated in the aorta but not the kidneys of spontaneously hypertensive rats, which exhibited hypertension but minor glomerulosclerotic changes. In conclusion, the LOX-1 upregulation in the kidney of DS 8% rats was parallel to glomerulosclerotic changes and renal dysfunction, suggesting a possible pathogenetic role for renal LOX-1 in the progression to hypertensive glomerulosclerosis.

Topics: Animals; Blood Pressure; Body Weight; Cells, Cultured; Collagen; Gene Expression; Glomerulosclerosis, Focal Segmental; Humans; Hypertension; Kidney; Kidney Glomerulus; Lipids; Male; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Receptors, LDL; Receptors, Oxidized LDL; Scavenger Receptors, Class E; Transforming Growth Factor beta; Transforming Growth Factor beta1

The purpose of this study was to develop DNA-RNA chimeric hammerhead ribozyme against transforming growth factor-beta(1) (TGF-beta(1)) mRNA as a gene therapy agent for arterial proliferative diseases.. A 38-base hammerhead ribozyme against rat TGF-beta(1) mRNA, to produce cleavage at the GUC sequence at nucleotide 825 according to the secondary structure of rat TGF-beta(1) mRNA was designed. To enhance its stability, we synthesized a DNA-RNA chimeric ribozyme with two phosphorothioate linkages at the 3'-terminal. We also synthesized a mismatch ribozyme with single base change in the catalytic loop region as a control. These ribozymes were delivered into rat vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats by lipofectin-mediated transfection, and their biological effects were investigated.. According to in vitro cleavage studies, the synthetic ribozyme can cleave the synthetic substrate RNA into two RNA fragments. Chimeric ribozyme significantly inhibited DNA synthesis in VSMC from SHR but not in cells from WKY rats. Mismatch ribozyme showed only a little effect on growth of VSMC from SHR. Chimeric ribozyme significantly inhibited proliferation of VSMC from SHR; in contrast, the proliferation of VSMC from WKY rats was significantly increased by this chimeric ribozyme. Mismatch ribozyme did not affect proliferation of VSMC from either rat strain. Chimeric hammerhead ribozyme to rat TGF-beta(1) dose-dependently inhibited TGF-beta(1) mRNA expression detected by reverse transcription and polymerase chain reaction analysis in VSMC from both rat strains. Chimeric hammerhead ribozyme to rat TGF-beta(1) also dose-dependently inhibited TGF-beta(1) protein production detected by Western blot analysis.. The present results demonstrated that our designed DNA-RNA chimeric hammerhead ribozyme to TGF-beta(1) mRNA might be a useful gene therapy agent for hypertensive vascular diseases.

Topics: Analysis of Variance; Animals; Blotting, Western; DNA; Genetic Engineering; Genetic Therapy; Hypertension; Models, Animal; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Catalytic; RNA, Messenger; Transforming Growth Factor beta

The present study examines the hypothesis that the elevated levels of transforming growth factor (TGF)-beta1 and interleukin (IL)-10 would be protective for the fetus survival during pregnancy-induced hypertension (PIH). Moreover, we evaluate the IL-12 and IL-15 serum concentrations and their relationships with PIH.. Serum samples were obtained before the onset of labor from control and PIH groups. Cytokine concentrations were determined by Enzyme-Linked Immunoadsorbent Assay.. Our data show that PIH women have significantly higher TGF-beta1 and IL-10 concentrations with respect to control groups (P = 0.0001). Similarly, macrophages from the PIH placentas produce in vitro more elevated TGF-beta1 and IL-10 levels compared to normal pregnant ones (P = 0.02), also in the absence of LPS stimulation. IL-12 and IL-15 serum concentrations were not detectable in all pregnant groups.. We have found that PIH women have elevated concentrations of anti-inflammatory/immunosuppressive cytokines, suggesting their important role in fetal allograft protection during the normal and pathological pregnancy.

Topics: Adult; Case-Control Studies; Cytokines; Decidua; Female; Humans; Hypertension; In Vitro Techniques; Interleukin-10; Interleukin-12; Interleukin-15; Macrophages; Pregnancy; Pregnancy Complications, Cardiovascular; Suppressor Factors, Immunologic; Transforming Growth Factor beta

to compare patients with abdominal aortic aneurysm (AAA) and aortic occlusive disease (AOD) with regard to risk factors for atherosclerosis, co-morbid conditions and inflammatory activity.. a total of 155 patients undergoing abdominal aortic surgery between January 1993 and October 1997: 82 (53%) had aneurysmal disease and 73 (47%) had occlusive disease. Principal risk factors were compared: age; gender; smoking; hypertension; hyperlipidaemia; diabetes mellitus; severe peripheral vascular disease (PVD) and ischaemic heart disease. Aortic wall tissue samples were obtained during surgery. A prospective blind analysis was performed for the presence of inflammatory cytokines TNF-alpha, IL-1 beta, IL-6 and TGF-beta.. the average age of AAA patients was 74 years (50-88), while that of AOD patients was 61 years (43-82) (p<0.0001). Diabetes mellitus was found to be much more prevalent in the AOD group (p<0.001), while hypertension and severe PVD were more prevalent in the AAA group (p<0.001). No differences were found concerning any of the risk factors. Inflammatory cytokine activity: AAA tissue samples contained significantly higher mean TNF-alpha and IL-6 levels compared to the AOD samples (5.6+/-2.7 x 10 E-4 vs. 4.4+/-2.7 x 10 E-5 atmoles/microl (p=0. 01), and 0.6+/-0.4 vs. 0.01+/-0.006 atmoles/microl (p=0.02) respectively). No differences were found related to IL-1 beta and TGF-beta.. (1) Patients with AAA have fewer atherosclerotic risk factors than do patients with AOD. (2) Patients with AAA and AOD have significantly different inflammatory activity. (3) The data supports the hypothesis that AAA and AOD are probably two different pathological entities.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Aortic Diseases; Coronary Disease; Diabetes Complications; Female; Humans; Hyperlipidemias; Hypertension; Interleukin-1; Interleukin-6; Male; Middle Aged; Polymerase Chain Reaction; Prospective Studies; Risk Factors; Sex Factors; Smoking; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vascular Diseases

To investigate how the interruption of the renin-angiotensin system (RAS) and reduction of blood pressure (BP) affect the lesions of chronic focal and segmental glomerulosclerosis (FGS), we studied the effects of high and low doses of angiotensin-converting enzyme inhibitors (temocapril - TEM) a newly developed ACE inhibitor with biliary tract excretion, on the hypertensive model of FGS. A high dose of TEM significantly lowered BP and suppressed both intense proteinuria and glomerular extracapillary lesions including macrophage infiltration. On the other hand, although a low dose of TEM did not significantly lower BP throughout the experimental period, it prevented renal lesions almost in the same manner as high-dose TEM with suppression of c-myc gene expression in glomeruli. These findings suggest that in PAN-induced chronic FGS, the systemic BP elevation could not be the major factor for the progression of renal damage which TEM could prevent without significant lowering of BP.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Antimetabolites, Antineoplastic; Bile; Blood Pressure; Blotting, Northern; Glomerulosclerosis, Focal Segmental; Hypertension; Immunohistochemistry; Male; Organ Size; Protamines; Proto-Oncogene Proteins c-myc; Puromycin Aminonucleoside; Rats; Rats, Inbred SHR; RNA, Messenger; Thiazepines; Transforming Growth Factor beta

Transforming growth factor-beta1 (TGF-beta1), a multifunctional cytokine with fibrogenic properties, has been implicated in the pathogenesis of the vascular and target organ complications of hypertension. TGF-beta1 may also regulate blood pressure via stimulation of endothelin-1 and/or renin secretion. Herein we explored the hypothesis that circulating levels of TGF-beta1 protein (quantified using a TGF-beta1-specific sandwich ELISA) are correlates of blood pressure levels. This hypothesis was tested in 98 stable end-stage renal disease (ESRD) patients. (The use of ESRD patients as the study cohort eliminates renal function-dependent alterations in circulating levels of TGF-beta1 protein.) In addition, in view of the previously reported correlation among TGF-beta1 DNA polymorphisms and systolic blood pressure, TGF-beta1 codon 25 genotype and alleles were identified in 71 hypertensive subjects and 57 normotensives using amplification refractory mutation system polymerase chain reaction. Our studies demonstrate for the first time that TGF-beta1 levels (209+/-13 ng/mL, mean+/-SEM) are positive correlates (Pearson correlation analysis) of mean arterial pressure (P=0.008), systolic pressure (P=0.02), and diastolic pressure (P=0. 01). We also report that a higher percentage of hypertensives (92%) compared with normotensives (86%) are homozygous for the arginine allele at codon 25. Our observations support the idea that genetically determined TGF-beta1 protein concentrations may play a role in blood pressure regulation in humans.

Topics: Amino Acid Substitution; Blood Pressure; Codon; Cohort Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Point Mutation; Polymerase Chain Reaction; Polymorphism, Genetic; Reference Values; Regression Analysis; Systole; Transforming Growth Factor beta

We have previously demonstrated that angiotensin II (Ang II) contributes to the increase in aortic transforming growth factor-beta(1) (TGF-beta(1)) mRNA levels in hypertensive rats. However, the molecular mechanism whereby Ang II promotes TGF-beta(1) expression in vascular smooth muscle cells (VSMCs) is poorly understood. In this study, we examined the role of extracellular signal-regulated kinase (ERK) in Ang II-mediated TGF-beta(1) expression in VSMCs and the role of Ang II in aortic ERK activity of stroke-prone spontaneously hypertensive rats. Treatment of quiescent VSMCs with 100 nmol/L Ang II induced rapid phosphorylation and activation of ERK1 and ERK2 with a peak at 5 minutes followed by an increase in activator protein-1 (AP-1) DNA binding activity, as shown by gel mobility shift assay. An increase in TGF-beta(1) mRNA was shown by Northern blot analysis. Treatment of VSMCs with PD98059, a specific inhibitor of the ERK pathway, attenuated both the activation of AP-1 and the increase in TGF-beta(1) mRNA induced by Ang II. Inhibition of Ang II-induced AP-1 activation with c-fos antisense oligodeoxynucleotide led to a significant reduction of TGF-beta(1) mRNA in VSMCs. Furthermore, in vivo treatment of stroke-prone spontaneously hypertensive rats with losartan, an Ang II type 1 receptor antagonist, decreased aortic ERK activity. Thus, we show that ERK, through AP-1 activation, is involved in Ang II-induced TGF-beta(1) mRNA expression in VSMCs and suggest that ERK may participate in vascular remodeling of hypertension. However, it remains to be determined whether the increase in TGF-beta(1) mRNA leads to the increase in its active protein.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Aorta; Calcium-Calmodulin-Dependent Protein Kinases; DNA-Binding Proteins; Enzyme Activation; Enzyme Inhibitors; Flavonoids; Hypertension; Male; Muscle, Smooth, Vascular; Oligonucleotides, Antisense; Phosphorylation; Proto-Oncogene Proteins c-fos; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Transcription Factor AP-1; Transforming Growth Factor beta

To evaluate effects of eicosapentaenoic acid (EPA), an n-3 polyunsaturated fatty acid, on the exaggerated growth of vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR).. Cultured VSMC were prepared by an explant method from thoracic aortas in 8-week-old male Wistar-Kyoto (WKY)/Izumo rats and SHR/Izumo. Effects of EPA on basal DNA synthesis, expression of growth factors and cyclin-dependent kinase 2 (cdk2) activity were examined in VSMC from WKY rats and SHR.. The cell cycles were synchronized with serum deprivation, then DNA synthesis in VSMC was measured by [3H]-thymidine incorporation. Fatty acid composition of the phospholipid fraction in VSMC was measured by gas chromatography. Expression of platelet-derived growth factor (PDGF) A-chain, transforming growth factor (TGF)-beta1 and basic fibroblast growth factor (bFGF) mRNAs was evaluated by reverse-transcription and polymerase chain reaction analysis. Cdk2 activity was determined by autoradiography after polyacrylamide gel electrophoresis of VSMC extracts that had been immunoprecipitated with anti-cdk2 antibody and protein A sepharose, and then incubated with 32P-ATP and histone H1.. High concentrations (40 and 80 micromol/I) of EPA significantly inhibited basal DNA synthesis in VSMC from both rat strains. Low dose (20 micromol/l) of EPA significantly inhibited basal DNA synthesis in VSMC from SHR, whereas the same dose of EPA stimulated DNA synthesis in VSMC from WKY rats. In analysis of fatty acid composition, low dose of EPA was considerably incorporated in VSMC. Low dose of EPA significantly inhibited angiotensin II- and phorbol ester milisterol-stimulated DNA synthesis in VSMC from both rat strains, whereas EPA did not affect PDGF-AA-stimulated DNA synthesis in VSMC from either rat strain. Low dose of other polyunsaturated fatty acids such as docosahexaenoic acid, arachidonic acid and linoleic acid did not significantly affect basal DNA synthesis in VSMC from either strain. Low dose of EPA significantly inhibited expression of TGF-beta1 mRNA in VSMC from SHR, whereas EPA did not affect expression of PDGF A-chain and bFGF mRNAs in VSMC from SHR. Cdk2 activity in VSMC from SHR was higher than that from WKY rats. Low dose of EPA inhibited cdk2 activity in VSMC from SHR, whereas it stimulated the activity in VSMC from WKY rats.. Low dose of EPA exerted specific inhibition of the exaggerated growth of VSMC from SHR through the suppression of TGF-beta.

Topics: Animals; CDC2-CDC28 Kinases; Cell Division; Cells, Cultured; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinases; Eicosapentaenoic Acid; Hypertension; Male; Muscle, Smooth, Vascular; Protein Serine-Threonine Kinases; Rats; Rats, Inbred SHR; Signal Transduction; Transforming Growth Factor beta

Topics: Black or African American; Blood Pressure; Gene Expression Regulation; Humans; Hypertension; Kallikreins; Polymorphism, Genetic; Promoter Regions, Genetic; Renal Insufficiency; Risk Factors; Transforming Growth Factor beta; United States; White People

Transforming growth factor-beta1 (TGF-beta1) stimulates vascular smooth muscle cell growth in spontaneously hypertensive rats (SHR), but inhibits cell growth in normotensive Wistar- Kyoto (WKY) rats. The present study was undertaken to test the hypothesis that TGF-beta1 might differentially modulate the activities of mitogen-activated protein (MAP) kinase family members (ERK, JNK and p38) in vascular smooth muscle cells of SHR and WKY rats.. MAP kinase activity was measured from cultured vascular smooth muscle cells in response to TGF-1 by specific substrate phosphorylation of myelin basic protein, GST-c-Jun and GST-ATF2.. Exposure of cultured vascular smooth muscle cells from SHR or WKY rats to TGF-beta1 resulted in a marked increase in the activity of ERK, but not of JNK or p38. The increase of ERK activity stimulated by TGF-beta1 appeared similar in time course and extent in both WKY and SHR cells, with increased activity peaking at 15 min of incubation. Epidermal growth factor (EGF) also stimulated the activity of ERK, in both WKY and SHR cells, but nor of JNK or p38, with stimulation of ERK activity by EGF occurring more rapidly in SHR cells than in those from WKY rats. Co-incubation of SHR cells with TGF-beta1 and EGF showed additive effect on ERK activity.. The results provide the first evidence that TGF-beta1 activates ERK in vascular smooth muscle cells of both normotensive and hypertensive rats. The matching response of ERK activation to TGF-1 in SHR cells suggests that the MAP kinase-signaling pathway remains largely unchanged in the regulation of vascular smooth muscle growth by TGF-1 in spontaneously hypertensive rats.

Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinases; Cells, Cultured; Epidermal Growth Factor; Glycogen Synthase Kinase 3; Growth Substances; Hypertension; JNK Mitogen-Activated Protein Kinases; Male; Mitogen-Activated Protein Kinases; Muscle, Smooth, Vascular; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reference Values; Transforming Growth Factor beta

The effects of angiotensin II (Ang II) on the expression and characteristics of transforming growth factor-beta (TGF-beta) receptors on vascular smooth muscle cells (VSMC) from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were investigated. TGF-beta-induced stimulation of DNA synthesis by VSMC from WKY rats was abolished with Ang II, whereas basal and TGF-beta-stimulated DNA synthesis by VSMC from SHR was increased with Ang II. Ang II stimulated DNA synthesis by VSMC from WKY rats in the presence but not in the absence of neutralizing antibody to TGF-beta1. Antibody to TGF-beta1 enhanced the stimulatory effect of Ang II on DNA synthesis by VSMC from SHR. Ang II increased the specific binding of TGF-beta to VSMC from WKY rats by increasing both the expression of the lower-affinity of TGF-beta receptors as well as the total number of TGF-beta binding sites. In contrast, VSMC from SHR showed a higher affinity and number of TGF-beta receptors in the absence of Ang II than did cells from WKY rats, and these parameters were not affected by Ang II. Ang II increased the expression of TGF-beta type I receptor mRNA in VSMC from WKY rats but had no effect of TGF-beta receptor type I or II mRNA in VSMC from SHR, which predominantly express the type II receptor. These results indicate that an increase in the expression of the TGF-beta type I receptor by Ang II may facilitate the ability of endogenous TGF-beta to counteract the stimulatory effect of Ang II on growth in VSMC from WKY rats, whereas endogenous TGF-beta induced by Ang II cannot counteract the growth-promoting action of Ang II in VSMC from SHR. The abnormal regulation of TGF-beta receptors by Ang II may be associated with the exaggerated growth of VSMC from SHR.

Topics: Angiotensin II; Animals; Cell Division; Cells, Cultured; Hypertension; Male; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Transforming Growth Factor beta; RNA, Messenger; Transforming Growth Factor beta

Previous studies have suggested that differences in vascular smooth muscle cell (VSMC) proliferative responses between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats can be attributed to transforming growth factor-beta (TGF-beta) actions. Because vascular collagen content is reported to be lower in SHR than in WKY rats, in this study we investigated in cell culture whether the differences in collagen content might also be attributed to differential actions of TGF-beta on VSMCs from the two strains. Exposure of VSMCs from WKY to the TGF-beta isoforms -beta1, -beta2, or -beta3 induced rapid, transient elevations in mRNAs encoding collagens alpha1(I), alpha2(I), and alpha1(III); maximum increases were apparent by 2 hours and ranged from twofold [collagen alpha1(III)] to ninefold [collagen alpha1(I)]. Thereafter they returned to near basal levels. When VSMCs from SHR were exposed to these TGF-beta isoforms, only reductions in collagen mRNA levels were observed, persisting for 24 hours. Basic fibroblast growth factor and epidermal growth factor, factors known to stimulate production of the TGF-beta1 isoform in VSMCs, also induced a pattern of gene responses similar to those induced by the TGF-beta isoforms in VSMCs from SHR and WKY rats. The simultaneous presence of TGF-beta did not affect the time course or magnitude of the changes in collagens alpha1(I), alpha2(I), or alpha1(III) mRNA levels in SHR or WKY VSMCs. Examination of the induction of c-myc mRNA and immunoreactive oncoprotein content indicated that c-myc is a likely contributor to the downregulation of the collagen gene activity in both SHR and WKY VSMCs despite the differential regulation of its mRNA by TGF-beta1 in the two VSMC lines. Together these data suggest that in VSMCs from SHR, a number of gene responses to TGF-beta, in addition to cell proliferation, appear to be abnormal compared with WKY rats, and the lower than normal collagen levels observed in the vasculature of SHR may be in part due to abnormalities in TGF-beta responsiveness.

Topics: Animals; Cell Nucleus; Collagen; Epidermal Growth Factor; Fibroblast Growth Factor 2; Hypertension; Male; Muscle, Smooth, Vascular; Proto-Oncogene Proteins c-myc; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor Protein-Tyrosine Kinases; RNA, Messenger; Transforming Growth Factor beta

Vasopressin (VP) is thought to play an important role in the pressor and proliferative responses of renal glomeruli. We have utilized the spontaneously hypertensive rat (SHR) model to determine if glomerular proliferation is induced by chronic infusion of exogenous VP. SHR were continuously infused with 0.1 ng/kg/min VP (H-VP group), 1.0 ng/kg/min (H-VP group), or vehicle alone (control group) for fifteen days using osmotic minipumps, and the histological alterations and level of expression of platelet-derived growth factor B-chain (PDGF-B) and transforming growth factor (TGF)-beta1 mRNA were determined. We observed no significant differences in systolic blood pressure, heart rate, serum electrolytes, protein and creatinine among the three groups of rats, but urine volume was found to be significantly decreased, and urine osmolality significantly increased, in the H-VP group. Kidney weight was significantly higher in the H-VP and L-VP groups than in the control group, and glomerular diameter was higher in the H-VP group. When we measured mesangial injury score and cellularity in the glomeruli of these animals, we observed VP dose-dependent proliferative changes. In the immunofluorescence study, although we did not find an obvious difference in depositions of collagen types III, IV and VI, alpha-smooth muscle actin and PDGF-B among the groups, the collagen type I and TGF-beta1 increased in several glomeruli in the H-VP group. Reverse transcription polymerase chain reaction (RT-PCR) revealed no significant differences in the glomerular levels of PDGF-B mRNA among the three groups of rats, but the level of expression of TGF-beta1 mRNA was significantly higher in the L-VP and H-VP groups than in the control group. These findings suggest that VP may contribute to glomerular proliferation, and that VP may exert its effects in part through the induction of TGF-beta1 expression. These results also raise the possibility that blockade of VP receptors may be useful in the treatment of some forms of glomerular disease.

Topics: Animals; Blood Chemical Analysis; Blood Pressure; Cell Division; Heart Rate; Hypertension; Kidney Glomerulus; Microscopy, Fluorescence; Organ Size; Platelet-Derived Growth Factor; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-sis; Rats; Rats, Inbred SHR; RNA, Messenger; Transforming Growth Factor beta; Vasopressins

Left ventricular hypertrophy (LVH) is characterized by remodeling of both myocyte and interstitial compartments of the heart. The aim of this investigation was to study the effects of angiotensin converting enzyme (ACE) inhibition on alterations in the composition of the interstitium in chronic pressure-overload hypertrophy.. LVH was induced in weanling rats by banding the ascending aorta. Animals with aortic banding received either vehicle (n = 20), hydralazine (20 mg/kg per day, n = 20), or the ACE inhibitor ramipril (10 mg/kg per day, n = 20) during weeks 6-12 after banding.. Compared with sham-operated, untreated rats (n = 20), aortic-banded vehicle and hydralazine-treated rats displayed substantially increased left ventricular weights and myocyte diameters whereas ramipril significantly blunted the hypertrophic response at the myocyte level (each P < 0.001) as well as the increase in left ventricular weight (each P < 0.01). In addition, image analysis revealed a significant induction of perivascular and interstitial tissue accumulation in vehicle- and hydralazine-treated rats (2.5-fold, each P < 0.0001). In contrast, ramipril-treated rats displayed attenuated interstitial and perivascular fibrosis, both being significantly diminished compared with vehicle- and hydralazine-treated rats (each P< 0.001). Further, vehicle- and hydralazine-treated rats were characterized by elevated steady-state messenger (m)RNA levels of fibronectin (2.7- and 2.8-fold, P< 0.005), collagen I (2.0- and 1.8-fold, P < 0.0005), collagen III (both 2.2-fold, P < 0.001) and laminin B (1.6- and 1.6-fold, P < 0.005). In parallel, the corresponding immunohistochemical signals were markedly enhanced in these groups. In comparison, ramipril significantly blunted the induction of collagen I and III, laminin B and fibronectin at both the mRNA and protein levels. These morphological and molecular differences between the hydralazine and ramipril groups could not be attributed to differences in left ventricular-pressures, which were markedly elevated in all aortic stenosis rats (1.9-fold, each P < 0.001 versus sham). In fact, given that ramipril but not hydralazine blunted the hypertrophic response to pressure overload, the echocardiographic measurements revealed that left ventricular systolic wall stress was higher in the ramipril group (70 +/- 1 versus 34 +/- 0.7 kdyn/cm2; P < 0.02).. ACE inhibition may limit both myocyte and interstitial remodeling despite ongoing cardiac pressure overload.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Extracellular Matrix Proteins; Fibronectins; Gene Expression; Hydralazine; Hypertension; Hypertrophy, Left Ventricular; Laminin; Male; Procollagen; Ramipril; Rats; Rats, Wistar; RNA, Messenger; Transforming Growth Factor beta

Topics: Coronary Disease; Genetic Predisposition to Disease; Humans; Hypertension; Myocardial Infarction; Polymorphism, Genetic; Transforming Growth Factor beta

Pregnancy after the onset of scleroderma is uncommon; therefore, placental findings and perinatal outcome have rarely been correlated. The histopathologic features of placentas from 13 pregnancies in eight women with scleroderma were recorded and correlated with the clinical features of the mother and fetus. Adverse perinatal outcome included intrauterine fetal demise in five, and previable or preterm delivery in four. A decidual vasculopathy was seen in 5 of the 13 placentas, four of which were associated with intrauterine fetal demise. Decidual blood vessels in the scleroderma patients were evaluated immunohistochemically for platelet-derived growth factor (PDGF), transforming growth factor beta1 (TGF-beta1), T-helper and T-suppressor lymphocytes, macrophages, immunoglobulin (Ig) M, and IgG, and compared with those from hypertensive and uncomplicated third-trimester pregnancies. The atherotic blood vessels in scleroderma were characterized by mural macrophages and IgM and IgG deposition and were similar to those seen in placentas from hypertensive pregnancies. CD8-positive T cells predominated in normal and hypertensive decidua compared with scleroderma, in which CD4-positive T cells were more frequent. No difference in PDGF or TGF-beta1 staining was found between scleroderma and control groups. In conclusion, decidual vasculopathy is common in scleroderma, is similar to that seen in hypertension, and is associated with poor perinatal outcome. A trend toward a reversed ratio of decidual CD4 to CD8-positive T cells is seen in scleroderma compared with hypertension and uncomplicated pregnancies. PDGF and TGF-beta1 do not appear to be involved in the pathogenesis of decidual vasculopathy in scleroderma.

Topics: Abortion, Spontaneous; Adolescent; Adult; Antigens, CD; Arteriosclerosis; Blood Vessels; CD4-CD8 Ratio; Decidua; Female; Fetal Death; Gestational Age; Humans; Hypertension; Immunoglobulins; Infant, Newborn; Male; Obstetric Labor, Premature; Platelet-Derived Growth Factor; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Scleroderma, Systemic; Transforming Growth Factor beta

A growing body of evidence indicates that the individual genetic background plays a role in the pathogenesis of diabetic glomerular disease by either favoring or protecting against injury produced by hyperglycemia. Two genetically related rat strains, the Milan normotensive strain (MNS) and the Milan hypertensive strain (MHS) display different susceptibilities to develop glomerulosclerosis with age. Glomerular sclerosing lesions occur in the MNS rats, which remain normotensive throughout their entire life-span, but not in the MHS rats, despite the presence of arterial hypertension. Previous studies have reported that extracellular matrix production and cell proliferation increased with donor-aging in mesangial cells isolated from MNS rats, but not in those from MHS rats, thus suggesting the existence of an inherited defect in the regulation of cell and matrix turnover, which translates into an abnormal response to growth-promoting stimuli favoring the development of glomerulosclerosis. In the study presented here, it was hypothesized that, in addition to donor-aging, other independent risk factors for the development of glomerular disease, such as metabolic injury by hyperglycemia, would be able to trigger and/or precipitate the occurrence of these changes in mesangial cells from the susceptible normotensive strain, but not in those from the protected hypertensive strain. To test this hypothesis, mesangial cells obtained from these rat strains (before the onset of either glomerulosclerosis or hypertension) were used to assess the effects of prolonged (4 wk) exposure to high (30 mmol/L) versus normal (5.5 mmol/L) glucose concentrations on extracellular matrix and cytokine production and cell proliferation. The accumulation and/or gene expression of the matrix components fibronectin, laminin, and collagen IV, and of the cytokines insulin-like growth factor-I (IGF-I) and transforming growth factor-beta (TGF-beta) did not change under normal glucose and increased progressively in response to high glucose in both MNS and MHS cells. These increases, with the exception of the increment in TGF-beta gene expression, were significantly more pronounced in MNS cells than in MHS cells. In contrast, the proliferative response to serum was not affected by high glucose, but increased in MNS cells, and decreased, although not significantly, in MHS cells during the 4-wk period, thus mimicking the changes previously observed in these rat strains as a function of age. These

Topics: Animals; Blood Glucose; Blood Pressure; Cell Division; Extracellular Matrix; Genetic Predisposition to Disease; Glomerular Mesangium; Glomerulosclerosis, Focal Segmental; Hypertension; Insulin-Like Growth Factor I; Rats; Rats, Inbred Strains; Rats, Mutant Strains; Reference Values; RNA, Messenger; Transforming Growth Factor beta

Cultured human peripheral blood monocytes are known to secrete and express transforming growth factor-beta (TGF-beta), a multifunctional cytokine that can be involved in myocardial and vascular remodeling. In addition, monocytes/macrophages have been demonstrated to be colocalized with fibrosis of hypertrophied heart and in the vascular wall of hypertensive vessels. In this study, we tested TGF-beta production and mRNA expression in peripheral blood monocytes from hypertensive patients with myocardial hypertrophy and increased carotid myointimal thickness with respect to healthy normotensive control subjects. We found an increased TGF-beta activity in the conditioned medium of monocytes from hypertensive patients compared with control subjects as evaluated by inhibition of [3H]thymidine incorporation by mink lung epithelial cells (-83% and -18% in hypertensive and normotensive subjects; P<.001). Western blot analysis confirmed a significant difference in the amount of TGF-beta protein secreted in the conditioned medium of hypertensive patients compared with that of normotensive subjects. Finally, we also observed a 4.2- and 5.5-fold increase in the amount of TGF-beta1 and TGF-beta2 transcripts, respectively. Our results indicate an upregulation of the TGF-beta system in the peripheral blood monocytes of hypertensive patients with cardiovascular structural changes, suggesting a possible role of TGF-beta monocyte production in hypertensive disease.

Topics: Biological Assay; Blotting, Northern; Blotting, Western; Cardiomegaly; Cells, Cultured; Culture Media; Data Interpretation, Statistical; DNA; Female; Gene Expression; Humans; Hypertension; Male; Middle Aged; Monocytes; RNA, Messenger; Transcription, Genetic; Transforming Growth Factor beta; Up-Regulation

Topics: Aminoglycosides; Animals; Anti-Bacterial Agents; Endothelins; Humans; Hypertension; Ion Channels; Kidney; Neoplasms; Polycystic Kidney Diseases; Sodium Channels; Transforming Growth Factor beta; Water-Electrolyte Imbalance

The spontaneously hypertensive rat (SHR) exhibits a transition from stable compensated left ventricular (LV) hypertrophy to heart failure (HF) at a mean age of 21 months that is characterized by a decrease in alpha-myosin heavy chain (alpha-MHC) gene expression and increases in the expression of the atrial natriuretic factor (ANF), pro-alpha1(III) collagen, and transforming growth factor beta1 (TGF-beta1) genes. We tested the hypotheses that angiotensin-converting enzyme inhibition (ACEI) in SHR would prevent and reverse HF-associated changes in gene expression when administered prior to and after the onset of HF, respectively. We also investigated the effect of ACEI on circulating and cardiac components of the renin-angiotensin system. ACEI (captopril 2 g/L in the drinking water) was initiated at 12, 18, and 21 months of age in SHR without HF and in SHR with HF. Results were compared with those of age-matched normotensive Wistar-Kyoto (WKY) rats, and to untreated SHR with and without evidence of HF. ACEI initiated prior to failure prevented the changes in alpha-MHC, ANF, pro-alpha1(III) collagen, and TGF-beta1 gene expression that are associated with the transition to HF. ACEI initiated after the onset of HF lowered levels of TGF-beta1 mRNA by 50% (P<.05) and elevated levels of alpha-MHC mRNA two- to threefold (P<.05). Circulating levels of renin and angiotensin I were elevated four- to sixfold by ACEI, but surprisingly, plasma levels of angiotensin II were not reduced. ACEI increased LV renin mRNA levels in WKY and SHR by two- to threefold but did not influence LV levels of angiotensinogen mRNA. The results suggest that the anti-HF benefits of ACEI in SHR may be mediated, at least in part, by effects on the expression of specific genes, including those encoding alpha-MHC, ANF, TGF-beta1, pro-alpha1(III) collagen, and renin-angiotensin system components.

Topics: Aging; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Atrial Natriuretic Factor; Captopril; Cardiomegaly; Gene Expression Regulation; Heart; Heart Failure; Hypertension; Male; Myosin Heavy Chains; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin; RNA, Messenger; Transcription, Genetic; Transforming Growth Factor beta

The renin-angiotensin system (RAS) has been implicated in the development of hypertensive glomerulosclerosis. However, there are no experimental findings clearly demonstrating activation of glomerular RAS in hypertensive nephropathy. Using the stroke-prone spontaneously hypertensive rat (SHRSP) as an animal model of hypertensive glomerulosclerosis, we examined the relationship between the sequential changes in urinary albumin excretion (UAE), renal morphology, and glomerular mRNA expression for transforming growth factor-beta (TGF-beta) and fibronectin (FN) and glomerular mRNA levels for RAS components, and determined the effects of the angiotensin II (Ang II) type 1 (AT-1) receptor antagonist (candesartan) and equihypotensive hydralazine on these parameters. In SHRSP, UAE was normal at nine weeks of age and increased by 12 weeks. Plasma renin activity, plasma Ang II concentration, and angiotensin converting enzyme (ACE) activity were not higher in 9- and 12-week-old SHRSP than in WKY. RNase protection assay revealed higher glomerular mRNA levels for angiotensinogen, ACE, and AT-1a and AT-1b receptors in 9-, 12-, and 14-week-old SHRSP than in WKY. The glomerular mRNA levels for TGF-beta and FN in SHRSP were increased from nine weeks of age. SHRSP had a greater glomerulosclerosis index (GSI) at 24 weeks of age than did WKY. Administration of candesartan for two weeks, but not of hydralazine, markedly reduced UAE and normalized mRNA levels for TGF-beta, FN, and RAS components. Candesartan administration for 12 weeks virtually prevented the progression of glomerulosclerosis in rats. We conclude that in SHRSP, RAS activation and increased sensitivity to Ang II in glomeruli play important roles in the progression of glomerulosclerosis.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Disease Progression; Fibronectins; Glomerulosclerosis, Focal Segmental; Hypertension; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta

Diastolic hypertension after renal transplantation leads to significant chronic morbidity and mortality. Recently, calcineurin phosphatase inhibition by cyclosporine or tacrolimus has been postulated to lead to diastolic hypertension through the induction of transforming growth factor-beta (TGF-beta) and resultant endothelin-mediated renal arteriolar vasospasm.. To investigate this hypothesis in humans, the allografts of 40 stable renal allograft recipients were biopsied 2 to 3 years after transplantation. Both cyclosporine and tacrolimus patients were included. Biopsies were divided and processed for histology and RNA extraction. RNA was then converted to cDNA and evaluated by semiquantitative polymerase chain reaction (actin-standardized, high-performance liquid chromatography-quantitated) for TGF-beta, endothelin, and renin transcription. Inflammatory cytokine gene transcription was also evaluated. Blood pressure was measured during the clinic check-in before biopsy. Variables were evaluated by Spearman rank correlation coefficient (rs) analysis.. Diastolic hypertension was prevalent in the study population, with 40% of individuals having diastolic pressure >90 mmHg. TGF-beta and endothelin transcription were detected in 88% of biopsies studied, and renin transcription was detected in 91%. Intragraft transcription of TGF-beta (rs=0.61, P=0.0003) and endothelin (rs=0.43, P=0.0188) was strongly correlated with increasing transcription intragraft renin. In turn, renin transcription was strongly correlated with increasing diastolic blood pressure (rs=0.55, P=0.0015). Histological correlation of fibrosis score did not predict the degree of hypertension, nor did it correlate with TGF-beta transcription. Inflammatory cytokine transcription was not related to renin transcription or diastolic hypertension but was correlated with histological evidence of immune graft injury.. These data support the hypothesis that posttransplant diastolic hypertension is a result of TGF-beta-induced, endothelin-mediated arteriolar vasoconstriction and subsequent activation of the renin-angiotensin pathway. These effects are independent of immune-mediated graft injury.

Topics: Adult; Biopsy; Blood Pressure; Cytokines; Diastole; Endothelins; Gene Expression; Humans; Hypertension; Kidney Transplantation; Polymerase Chain Reaction; Renin; RNA, Messenger; Transcription, Genetic; Transforming Growth Factor beta

This study was performed to investigate the possible association between preeclampsia and the plasma concentrations of Lp(a) lipoprotein and TGF-beta1 in a large series of patients. Additionally, correlation between the concentrations of these molecules and the severity of preeclampsia or fetal growth retardation was evaluated. Following clinical examination and biochemical analyses, both electroimmunoassay and RIA technique were used for quantitative determinations of plasma Lp(a) lipoprotein. ELISA technique was used to measure the active form of TGF-beta1 in plasma of pregnant normotensive and preeclamptic women. We examined 154 women with preeclampsia (preeclampsia group) and 76 healthy, pregnant normotensive women (control group). The preeclampsia group was further divided into the following subgroups: mild preeclampsia, severe preeclampsia and preeclampsia with fetal growth retardation. Plasma levels of Lp(a) lipoprotein were lower in the total preeclampsia group as well as in all preeclampsia subgroups (5.45+/-7.41, 5.58+/-8.02, 5.08+/-5.38, and 4.32+/-5.28 mg/dl in the total preeclampsia group, and in subgroups with mild preeclampsia, severe preeclampsia, and preeclampsia with fetal growth retardation, respectively) than in the control group (7.84+/-9.26 mg/dl) as determined by quantitative electroimmunoassay. Corresponding results were obtained with a radioimmunoassay (166.03+/-200.2 U/l in the total preeclampsia group vs. 229.18+/-257.7 U/l in controls). There was good correlation between the two methods used for Lp(a) lipoprotein measurement. The differences between controls and the total preeclampsia group as well as each preeclampsia subgroup were statistically significant by a non-parametric test (one-way Kruskal-Wallis test). Plasma concentrations of the active form of TGF-beta1 were increased in all preeclampsia subgroups as well as in the total group (5.63+/-1.68 ng/ml) compared to controls (4.67+/-1.33 ng/ml). This increase in TGF-beta1 was statistically highly significant. Plasma concentrations of Lp(a) lipoprotein and the active form of TGF-beta1 did not differ significantly between the preeclampsia subgroups. The outcome of this study may suggest involvement of both parameters in the pathophysiology of preeclampsia and may substantiate the notion of a multifactorial etiology of the disease.

Topics: Adult; Arteriosclerosis; Birth Weight; Blood Pressure; Female; Fetal Growth Retardation; Gestational Age; Humans; Hypertension; Lipoprotein(a); Maternal Age; Pre-Eclampsia; Pregnancy; Risk Factors; Transforming Growth Factor beta

To assess the chronic in vivo effects of OPC-21268, a vasopressin-V1 receptor antagonist, on renal injury, we investigated the mRNA expressions of platelet-derived growth factor (PDGF) B-chain, transforming growth factor (TGF)-beta1 and proliferating cell nuclear antigen (PCNA) in the glomeruli of spontaneously hypertensive rats (SHR) treated with OPC-21268 for 3 weeks. SHR aged 10 weeks were given 2% NaCl in drinking water for 3 weeks. The OPC group was fed a 0.5% OPC-21268-containing diet for 3 weeks and the control group was given a normal diet. There were no significant changes in the time course of systolic blood pressure, heart rate, urine volume, or urinary sodium, protein and N-acetyl-beta-glucosaminidase (NAG) excretion between the two groups. Serum electrolytes, protein and creatinine levels also did not differ between the groups. The mRNA expressions of PDGF B-chain, TGF-beta1 and PCNA in the glomerulus were examined using reverse transcriptase-polymerase chain reaction (RT-PCR) methods. The mRNA expressions of PDGF B-chain and PCNA among these were significantly suppressed in the OPC group. No significant differences in renal histology including the organ weights were found between the two groups; however, the glomerular size tended to be enlarged in the OPC group. These findings suggest that chronic V1-receptor blockade directly inhibits the glomerular proliferative injury of salt-loaded SHR at the established hypertension stage.

Topics: Acetylglucosaminidase; Animals; Antidiuretic Hormone Receptor Antagonists; Blood Pressure; Body Weight; Growth Substances; Heart Rate; Hypertension; Kidney Glomerulus; Organ Size; Piperidines; Platelet-Derived Growth Factor; Polymerase Chain Reaction; Proliferating Cell Nuclear Antigen; Proteinuria; Quinolones; Random Allocation; Rats; Rats, Inbred SHR; RNA, Messenger; Sodium; Transforming Growth Factor beta; Urine

To investigate the role of angiotensin II (ANG II) in the development of hypertension induced by reduced renal mass (RRM) and the gene expression of ANG II type 1 (AT1) receptors in the remnant renal tissue, four groups of rats were given 1% NaCl in water and subjected to RRM, RRM+ ramipril, RRM+ losartan, or sham surgery (control). Tail-cuff systolic blood pressure was significantly higher in RRM rats than in the other three groups. Northern blot showed that AT1 gene expression was significantly decreased in RRM, RRM + ramipril, or RRM + losartan vs. control. There was no significant difference among the three RRM groups. Renal transforming growth factor-beta 1 (TGF-beta 1) mRNA levels were increased threefold (P < 0.05) in RRM, RRM+ ramipril, and RRM+ losartan vs. control. There was no significant difference among the three RRM groups. We conclude that the development of RRM hypertension is ANG II dependent but not mediated by AT1 gene expression. RRM downregulates AT1 mRNA and upregulates TGF-beta 1 mRNA in the remnant renal tissue, regardless of blood pressure or plasma levels of ANG II, suggesting that these gene responses are triggered by an effect of local injury.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Gene Expression; Hypertension; Imidazoles; Losartan; Male; Nephrectomy; Ramipril; Rats; Rats, Wistar; Receptors, Angiotensin; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta

The profile of endothelin-1 (ET-1) release from cultured vascular endothelial cells (ECs) obtained from deoxycorticosterone acetate (DOCA)-salt hypertensive rats, was examined and compared with that from normotensive sham rats. ET-1 release from ECs was increased in a time-dependent manner, and the level of DOCA-salt hypertensive rats was higher than that of sham rats. Incubation of ECs with transforming growth factor (TGF)-beta 1 or thrombin resulted in a significant increase in the ET-1 release, while FK409, a novel nitric oxide donor, produced a dose-dependent decrease in the release. In the case of ECs from DOCA-salt hypertensive rats, the potencies of TGF-beta 1- or thrombin-induced action was much less than that seen with sham rats, while the difference of reactivity to FK409 was not observed between ECs of DOCA-salt rats and sham rats. Thus, ET-1 production in ECs appears to be up-regulated in DOCA-salt hypertensive rats. In addition, there seems to be an abnormalities in the signaling pathway via TGF-beta 1- or thrombin-induced enhancement of ET-1 production in ECs of DOCA-salt hypertensive rats.

Topics: Animals; Aorta; Cells, Cultured; Desoxycorticosterone; Endothelins; Endothelium, Vascular; Hypertension; Kinetics; Male; Nitro Compounds; Rats; Rats, Sprague-Dawley; Reference Values; Sodium Chloride; Thrombin; Transforming Growth Factor beta; Vasodilator Agents

Our previous study in vivo suggested that vascular smooth muscle cells (VSMCs) in stroke-prone spontaneously hypertensive rats (SHRSP) were vulnerable when plasma components were deficient. Therefore, we cultured VSMCs isolated from normotensive and hypertensive rats to clarify the weakness of VSMCs isolated from hypertensive rats and maintained in plasma-deficient conditions by employing ultrastructural and biochemical analyses. VSMCs, obtained from normotensive rats and cultured without fetal bovine serum (FBS) for 1 week, were intact and well differentiated; without FBS for 2 weeks retained their original structures except for several degenerative changes. VSMCs, obtained from hypertensive rats and cultured without FBS for 2 weeks, were extensively damaged and lost their cell organelles. Apoptotic bodies were frequently observed. We also cultured VSMCs in medium containing a variety of growth factors. VSMCs obtained from normotensive rats and cultured with epidermal growth factor or insulin-like growth factor-1 for 2 weeks were almost intact, as were VSMCs from hypertensive rats, although some degenerative changes of cell organelles were observed. VSMCs from hypertensive rats, maintained with platelet-derived growth factor-BB or basic fibroblast growth factor, were generally in poor condition. Thus VSMCs from hypertensive rats have hereditary weaknesses in cell survival including apoptosis and require specific growth factors for their maintenance.

Topics: Animals; Cattle; Cerebrovascular Disorders; Fibroblast Growth Factors; Growth Substances; Hypertension; L-Lactate Dehydrogenase; Muscle, Smooth, Vascular; Platelet-Derived Growth Factor; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Somatomedins; Transforming Growth Factor beta

We undertook this study to investigate the regulatory mechanism of cardiac gene expression in spontaneously hypertensive rats (SHR) during development. We measured cardiac mRNAs by Northern blot analysis. In 9-week-old SHR at the very early stage of cardiac hypertrophy, the expression of various cardiac genes related to the regulation of cardiac contraction and relaxation was already significantly changed compared with control Wistar-Kyoto rats, indicating that cardiac molecular changes are responsible for cardiac remodeling or the modulation of cardiac performance in SHR. We gave various types of antihypertensive drugs, at oral doses causing a mild and comparable hypotensive effect, to 27-week-old SHR to examine the effects on the altered cardiac gene expression. Imidapril, an angiotensin-converting enzyme inhibitor, normalized the increased gene expression of atrial natriuretic polypeptide and collagen types I and III and the decreased expression of alpha-myosin heavy chain in SHR heart. Atenolol (a beta 1-blocker) combined with doxazosin did not affect cardiac ANP and alpha-myosin heavy chain expression of SHR but normalized the increased collagen expression. In contrast, despite a hypotensive effect comparable to these two drug treatments, doxazosin (an alpha 1-blocker) alone or manidipine (a calcium antagonist) did not normalize these altered gene expressions of SHR. These results show that the cardiac renin-angiotensin system is involved in the altered cardiac gene expression in SHR. The beta 1- but not alpha 1-adrenergic receptor is also responsible for the increased cardiac collagen expression in SHR.

Topics: Actins; Aging; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Collagen; Gene Expression Regulation; Heart Rate; Hypertension; Male; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta) is a potent inducer of extracellular matrix production and of fibrogenesis and has been associated with the occurrence of diabetic micro- and macrovascular complications. Our aim was to determine whether circulating levels of TGF-beta 1 are altered in NIDDM and, if so, whether they are correlated with blood glucose and show an association with diabetic complications.. Plasma levels of TGF-beta 1 were determined by enzyme-linked immunosorbent assay in 44 NIDDM patients and 28 control subjects of comparable age and weight and were correlated with parameters of metabolic control and the occurrence of micro- and macrovascular complications.. TGF-beta 1 was significantly elevated in NIDDM (7.9 +/- 1.0 ng/ml), as compared with control subjects (3.1 +/- 0.4 ng/ml, P < 0.001) and correlated with glycosylated hemoglobin (r2 = 0.42; P < 0.001). Thrombocyte levels of TGF-beta 1 were similar in control subjects (54 +/- 7 pg/ml, n = 16) and diabetic patients (61.6 +/- 18 pg/ml, n = 13; P = 0.357). Elevated TGF-beta 1 levels were associated with retinopathy and neuropathy.. We conclude that plasma levels of TGF-beta 1 are elevated in NIDDM patients and may be related to average blood glucose. Preliminary data suggest that they may contribute to the occurrence of diabetic complications.

Topics: Aged; Biomarkers; Blood Glucose; Coronary Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Hypertension; Male; Middle Aged; Reference Values; Regression Analysis; Statistics, Nonparametric; Transforming Growth Factor beta

We have previously reported that renal mRNA levels for transforming growth factor-beta 1, fibronectin, and collagens were increased in 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) with severe nephrosclerosis. To elucidate the mechanism of hypertension-induced nephrosclerosis, we examined gene expression and localization of transforming growth factor-beta 1 and cellular phenotype in the kidney of 25-week-old SHRSP with moderate renal damage. Renal mRNA was measured by Northern blot analysis. The localization of transforming growth factor-beta 1 and cellular phenotype was determined by immunohistochemistry. In the kidney of 25-week-old SHRSP, renal transforming growth factor-beta 1 mRNA was elevated compared with Wistar-Kyoto rats (WKY), whereas renal collagen mRNAs of SHRSP were not increased. Immunoreactive transforming growth factor-beta 1 in SHRSP was mainly localized in glomerular cells. Furthermore, alpha-smooth muscle actin and desmin were significantly expressed in SHRSP glomerular cells, in contrast to negligible expression of these proteins in WKY. alpha-Smooth muscle actin staining was also observed in interstitial cells, and vimentin, another phenotypic marker, was expressed in atrophic tubular cells of SHRSP, despite no staining of these proteins in WKY. Furthermore, all these phenotypic changes in SHRSP were associated with increased cell proliferation, as shown by the increased number of proliferating cell nuclear antigen-positive cells. Treatment of SHRSP with cilazapril and nifedipine (from the age of 13 to 25 weeks) prevented the increase in transforming growth factor-beta 1 expression and the cellular phenotypic modulation and was accompanied by a reduction of urinary albumin excretion and inhibition of cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Actins; Animals; Blotting, Northern; Cell Division; Cilazapril; Gene Expression; Genetic Markers; Hypertension; Immunohistochemistry; Kidney; Kidney Glomerulus; Male; Nephrosclerosis; Nifedipine; Phenotype; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Staining and Labeling; Transforming Growth Factor beta; Vimentin

The modulatory effects of transforming growth factor beta 1 (TGF beta 1) on the angiotensin II (Ang II)-induced increase in cytosolic free calcium concentration ([Ca2+]i) were investigated in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). [Ca2+]i in VSMC was measured using the fluorescent dye fura-2. When TGF beta 1 was applied 30s prior to Ang II, the Ang II-induced [Ca2+]i increase was significantly enhanced in VSMC from SHR (P < 0.05 compared to control), whereas after the preincubation with TGF beta 1 for 30 min, the Ang II-induced [Ca2+]i increase was significantly reduced in VSMC from both strains. Using the manganese-quenching technique, it was confirmed that short-term exposure to TGF beta 1 enhanced the Ang II-induced trans-plasma-membrane calcium influx in SHR. The inhibition of protein kinase C by calphostin C abolished the stimulatory effect of TGF beta 1 on the Ang II-induced [Ca2+]i increase. It is concluded that TGF beta 1 modulates the Ang II-induced calcium handling in VSMC.

Topics: Angiotensin II; Animals; Aorta, Thoracic; Calcium; Cells, Cultured; Cytosol; Hypertension; Male; Muscle, Smooth, Vascular; Naphthalenes; Protein Kinase C; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetradecanoylphorbol Acetate; Transforming Growth Factor beta

TCV-116 [(+/-)-(cyclohexyloxycarbony-loxy)ethyl2-ethoxy-1-[[2' -(1H- tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate ], a nonpeptide selective angiotensin II type I receptor (AT1 receptor) antagonist, at the dose of 0.1, 1 or 10 mg kg-1 day-1, was orally given to 22-week-old stroke-prone spontaneously hypertensive rats (SHRSP) for 10 weeks (from the age of 22-32 weeks) to examine the effects on gene expression of transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix proteins in the heart and blood vessels. Tissue messenger RNA (mRNA) was measured by northern blot analysis, with a specific complementary DNA probe. In the heart, left ventricular mRNA levels for fibronectin; types I, III and IV collagen; and laminin were significantly higher in SHRSP than control Wistar-Kyoto rats. In the mesenteric artery and aorta of SHRSP, TGF-beta 1 mRNA and the mentioned extracellular matrix protein mRNAs were increased compared with Wistar-Kyoto rats. Thus, the expression of various genes was up-regulated in cardiovascular tissues of SHRSP. Treatment of SHRSP with TCV-116 suppressed the gene expression of the mentioned extracellular matrix proteins and TGF-beta 1 in both heart and blood vessels in a dose-dependent fashion. Furthermore, TCV-116 regressed cardiac hypertrophy and lessened the medial hypertrophy of the aorta in SHRSP. These results show that angiotensin AT1 receptor antagonist in vivo can inhibit the gene expression of TGF-beta 1 and extracellular matrix proteins in hypertensive cardiovascular tissues. These effects may contribute to the beneficial effects of AT1 receptor antagonist on hypertensive cardiac hypertrophy and vascular thickening.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Aorta; Benzimidazoles; Biphenyl Compounds; Cardiomegaly; Enalapril; Extracellular Matrix Proteins; Gene Expression Regulation; Hypertension; Male; Mesenteric Arteries; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta

To clarify whether the growth inhibitors, transforming growth factor-beta 1 (TGF-beta 1), heparin, and interferon-gamma (IFN-gamma) contribute to the development of vascular hypertrophy in spontaneously hypertensive rats (SHR), the growth of vascular smooth muscle cells (VSMC) was evaluated both for cell numbers over a period of 4 days, and [3H]thymidine incorporation over 24 h. Heparin and IFN-gamma inhibited the proliferation of VSMC from SHR and Wistar-Kyoto (WKY) rats. TGF-beta 1 enhanced SHR-VSMC proliferation by 16.6 +/- 8.9%; in contrast TGF-beta 1 inhibited WKY-VSMC proliferation by 60.5 +/- 7.4%. There was no difference in affinity, number of binding sites, or subtype expression of TGF-beta 1 receptor between SHR-VSMC and WKY-VSMC. This evidence suggests that the signal transduction system of TGF-beta 1 either the receptor itself or downstream signaling molecules, may be altered in SHR-VSMC versus WKY-VSMC. This abnormal responsiveness to TGF-beta 1 is involved in the proliferative characteristics of SHR-VSMC. Therefore, TGF-beta 1 could contribute to the development of hypertension or vascular hypertrophy in SHR.

Topics: Animals; Aorta, Thoracic; Cell Division; Cells, Cultured; DNA; Hypertension; Hypertrophy; Male; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta

Topics: Animals; Cardiovascular Diseases; DNA, Antisense; Genes, ras; Hypertension; Molecular Sequence Data; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Antisense; Transcription, Genetic; Transforming Growth Factor beta

Rats harboring the mouse Ren-2 transgene develop hypertension despite low levels of plasma renin. We determined the extent of left ventricular remodeling present in Ren-2 rats at 16 weeks of age by measuring blood pressure, ratio of heart weight to body weight, left ventricular wall thickness, passive (diastolic) left ventricular compliance, and left ventricular collagen content using hydroxyproline and collagen area fraction. Changes in perivascular fibronectin and collagen type I and III were examined with immunohistochemistry. Blood pressure values at time of death were 244 +/- 15 mm Hg for Ren-2 rats (mean +/- SD, n = 5). Ratios of heart weight to body weight (grams per kilogram) for Ren-2 animals were 4.1 +/- 0.2 versus 3.1 +/- 0.1 for controls (n = 6, P < .001). Wall thickness values for control animals were 2.6 +/- 0.1 versus 4.1 +/- 0.4 mm for Ren-2 animals (P < .001). Left ventricular Ren-2 hydroxyproline measurements were significantly decreased (3.4 +/- 0.2 versus 4.7 +/- 0.9 mg/g dry wt for controls). Significant decreases of approximately 30% were also observed in collagen area fraction in Ren-2 rats. Immunohistochemical and picrosirius red staining indicated increased amounts of perivascular fibrosis in all Ren-2 animals (when compared with controls) with enhanced levels of perivascular fibronectin and type I and type III collagen proteins. Left ventricular compliance measurements indicated a decrease in left ventricular volume for all left ventricular pressures (P = .07).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Genetically Modified; Collagen; Compliance; Hypertension; Mice; Myocardium; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Transforming Growth Factor beta; Ventricular Function, Left

To investigate the characteristics and expression of transforming growth factor (TGF)-beta receptor subtypes on vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats.. The effects of TGF-beta 1 on DNA synthesis were evaluated by [3H]-thymidine incorporation into quiescent VSMC plated at high (5 x 10(4) cells/cm2) or low (5 x 10(3) cells/cm2) cell density. Specific binding of TGF-beta to VSMC was assessed by incubation of the cells with [125I]-TGF-beta 1. Affinity labelling of receptor subtypes was achieved by exposure of the cells to [125I]-TGF-beta 1 and cross-linking with disuccimidyl suberate.. VSMC from SHR displayed a biphasic DNA synthesis response to TGF-beta 1 at high cell density, with DNA synthesis stimulated by low concentrations of TGF-beta 1 but not by high concentrations, whereas at low cell density there was a small increase in DNA synthesis in response to TGF-beta 1. TGF-beta 1 inhibited DNA synthesis in VSMC from WKY rats at both high and low cell densities. Binding assays revealed that VSMC from SHR had a larger number of TGF-beta receptors and a higher affinity for TGF-beta at high and at low cell densities. The affinity labelling with [125I]-TGF-beta 1 revealed the presence of receptor subtypes with relative molecular masses of 280-300, 85, 70, 60 and 50 x 10(3) on vascular smooth muscle cells from both rat strains at high cell density. The abundance of the 85 x 10(3) molecular mass receptor subtype was greater in VSMC from SHR. The 85 x 10(3) molecular mass receptor subtype was not detected on VSMC from either strain at low cell density.. The present results suggest a different expression of TGF-beta receptor subtypes on VSMC from SHR and WKY rats. These differences may account for the exaggerated proliferative response of VSMC from SHR to TGF-beta.

Topics: Animals; Cells, Cultured; DNA; Hypertension; Male; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta

The in vivo effects of alacepril (1-[(S)-3-acetylthio-2-methylpropanoyl]- L-prolyl-L-phenylalanine), an angiotensin converting enzyme inhibitor, and SC-52458 (5-[(3,5-dibutyl-1H-1,2,4-triazol-1- yl)methyl]-2-[2-(1H-tetrazol-5-ylphenyl)]pyridine), an angiotensin AT1 receptor antagonist, were examined on the cardiac and aortic gene expressions of extracellular matrices and TGF-beta 1 in young spontaneously hypertensive rats (SHR). In SHR, types I and III collagen mRNAs were increased in the left ventricle, and in contrast, fibronectin, collagen IV, and transforming growth factor-beta 1 (TGF-beta 1) mRNAs were increased in aorta, compared with those in Wistar-Kyoto rats. All the enhanced mRNAs in both organs in SHR were significantly inhibited by the short-term treatment with the above two drugs. Thus, angiotensin AT1 receptor may play an important role in the regulation of extracellular matrices and TGF-beta 1 expressions in SHR.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Blotting, Northern; Captopril; Collagen; Extracellular Matrix; Gene Expression Regulation; Heart Ventricles; Hypertension; Male; Organ Size; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta

Recent evidence indicates that transforming growth factor-beta 1 (TGF-beta 1) plays an important role in renal fibrosis via stimulation of extracellular matrix synthesis. The present study was undertaken to investigate the role of angiotensin II type I receptor (AT1 receptor) in hypertension-induced renal injury. Twenty-two-week-old stroke-prone spontaneously hypertensive rats (SHRSP), which had established hypertension and moderate renal damage, were orally given TCV-116, a selective non-peptide AT1 receptor antagonist (0.1, 1 or 10 mg/kg/day), enalapril (10 mg/kg/day) or vehicle once a day for 10 weeks. At the end point of the treatment, we examined renal function, the gene expressions of TGF-beta 1 and extracellular matrix components in the interstitium [collagen types I (COI) and III (COIII), fibronectin (FN)] and the basement membrane (COIV and laminin), and renal microscopic morphology in rats aged 32 weeks. In vehicle-treated 32 week-old SHRSP with renal dysfunction and nephrosclerosis, renal mRNA levels for TGF-beta 1, COI, COIII, FN, COIV were all several-fold higher than in WKY. Thus, renal TGF-beta 1 gene expression was enhanced in SHRSP, which may contribute to the increased renal expressions of COI, COIII, FN, COIV in SHRSP. Treatment with TCV-116 (0.1 mg/kg/day) in SHRSP, in spite of no reduction of blood pressure, decreased renal mRNA levels for TGF-beta 1, COI, COIII, FN, COIV, being accompanied by the significant decrease in urinary protein and albumin excretion, blood urea nitrogen and plasma creatinine. Treatment with TCV-116 (10 mg/kg/day) in SHRSP decreased mRNAs for TGF-beta 1, COI, COIII, FN and COIV to almost the same levels as WKY, being associated with normalization of urinary protein and albumin excretion and the prevention of nephrosclerosis, as judged by microscopic histological observations. On the other hand, the effects of enalapril (10 mg/kg/day) on the above mentioned mRNA levels, renal function and renal morphology were weaker than those of TCV-116 (10 mg/kg/day) and were as much as TCV-116 (1 mg/kg/day). These results suggest that independently of hypotensive action, AT1 receptor antagonist has a potent renal protective effect by inhibiting the gene expression of renal TGF-beta 1 and extracellular matrix components.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Benzimidazoles; Biphenyl Compounds; Enalapril; Extracellular Matrix Proteins; Gene Expression; Hemodynamics; Hypertension; Kidney; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Angiotensin; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta

To investigate the role of angiotensin II (Ang II) in hypertension-induced tissue injury, we gave TCV-116 (1 mg/kg per day PO), a nonpeptide Ang II type I receptor antagonist, or enalapril (10 mg/kg per day PO) to deoxycorticosterone acetate (DOCA)-salt hypertensive rats for 3 weeks and examined the effects on tissue mRNA levels for transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix components. Tissue mRNA levels were measured by Northern blot analysis. Renal mRNA levels for TGF-beta 1; types I, III, and IV collagen; and fibronectin in DOCA-salt hypertensive rats were increased by severalfold (P < .01) compared with sham-operated rats. In the aorta of DOCA-salt hypertensive rats, TGF-beta 1 and fibronectin mRNA levels were increased, but types I, III, and IV collagen mRNAs did not increase. In the heart, increased mRNA was found only for fibronectin. Thus, these gene expressions are regulated in a tissue-specific manner. TCV-116 or enalapril did not lower blood pressure in DOCA-salt hypertensive rats. However, the increase in renal mRNAs for TGF-beta 1 and extracellular matrix components in DOCA-salt hypertensive rats was significantly inhibited by treatment with TCV-116 or enalapril, which was associated with a significant decrease in urinary protein and albumin excretions and histological improvement of renal lesions. In contrast, in the aorta and heart these gene expressions were not affected by TCV-116 or enalapril. Thus, local Ang II may contribute to renal injury of DOCA-salt hypertension by stimulating the gene expression of TGF-beta 1 and extracellular matrix components.

Topics: Angiotensin II; Animals; Benzimidazoles; Biphenyl Compounds; Collagen; Desoxycorticosterone; Enalapril; Hypertension; Kidney; Kidney Diseases; Male; Organ Size; Rats; Rats, Wistar; Renin; RNA, Messenger; Sodium Chloride; Tetrazoles; Transforming Growth Factor beta

Cultured vascular smooth muscle cells derived from the spontaneously hypertensive rat (SHR) are known to replicate more rapidly than cells from the normotensive Wistar-Kyoto (WKY) rat. In this study we compared the responses of vascular smooth muscle cells from the two strains to transforming growth factor-beta 1 (TGF-beta 1) and evaluated its potential to account for the different growth properties of these cells in response to a number of vascular-derived growth factors. TGF-beta 1 potentiated the proliferative effects of epidermal growth factor, basic fibroblast growth factor, or the different isoforms of platelet-derived growth factor on vascular smooth muscle cells from SHR but inhibited growth factor-stimulated proliferation of vascular smooth muscle cells from WKY rats. These differential effects of TGF-beta 1 on proliferation could not be attributed to alterations in the expression of the type I, II, or III TGF-beta receptors but appeared more related to the ability of cells to autoinduce the TGF-beta 1 gene. TGF-beta 1 caused a time-dependent increase in its own mRNA levels in vascular smooth muscle cells of WKY rats but attenuated levels in vascular smooth muscle cells of SHR. This effect was specific to TGF-beta 1 autoinduction since similar elevations in TGF-beta 1 mRNA levels were observed when vascular smooth muscle cells from the two rat strains were exposed to phorbol myristate acetate, basic fibroblast growth factor, or platelet-derived growth factor-BB.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cell Division; Cells, Cultured; DNA; Gene Expression Regulation; Hypertension; Male; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Transforming Growth Factor beta; Transcriptional Activation; Transforming Growth Factor beta

1. This study examined and compared the actions of transforming growth factor-beta 1 (TGF-beta 1), heparin, dexamethasone and interferon-gamma on platelet-derived growth factor-BB (PDGF-BB)-stimulated proliferation of vascular smooth muscle cells (VSMC) from normotensive, Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). 2. Heparin, dexamethasone and interferon-gamma all inhibited VSMC proliferation stimulated by PDGF-BB in both SHR and WKY rats. There was no difference (P > 0.05) in their inhibitory effects, which varied between 40 and 85% for the different agents. 3. Similarly, TGF-beta 1 inhibited PDGF-BB-stimulated VSMC proliferation in WKY rats by approximately 50%. In contrast, TGF-beta 1 potentiated growth factor action on cell proliferation in the SHR by approximately 40%. 4. Specific TGF-beta 1-stimulated regulatory mechanisms involved in the inhibition of proliferation are absent in SHR and this defect may contribute to the vascular hypertrophy which is apparent in genetic hypertension.

Topics: Animals; Cell Division; Cells, Cultured; Dexamethasone; Heparin; Hypertension; Interferon-gamma; Muscle, Smooth, Vascular; Platelet-Derived Growth Factor; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Transforming Growth Factor beta

To gain insight into the mechanisms which contribute to the development of vascular hypertrophy in the spontaneously hypertensive rat (SHR).. These experiments were performed under conditions which most closely mimic the growth of smooth muscle in blood vessels, i.e. once cell-cell contact has been achieved.. A comparison of the growth characteristics (growth rates and cell density at quiescence) of vascular smooth muscle cells (VSMC) from SHR and normotensive Wistar-Kyoto (WKY) rats.. In the presence of foetal calf serum (1, 2.5, 5 and 10%), early passaged VSMC from SHR exhibited higher growth rates and reached higher densities at quiescence than VSMC from WKY rats. Accelerated growth rates could not be attributed to differences in cell-cell interactions. Also, growth rates and cell density at quiescence appear to be regulated by distinct mechanisms. Transforming growth factor-beta 1 (TGF-beta 1) caused an inhibition of serum-stimulated proliferation of confluent VSMC from WKY rats. In contrast, TGF-beta 1 had little, if any, inhibitory action upon the growth of VSMC from SHR. Scatchard analysis of 125I-TGF-beta 1 binding to VSMC from both strains yielded a single class of high affinity binding sites.. VSMC from SHR exhibit enhanced proliferation, attain a higher cell density at quiescence and are less susceptible to growth inhibition by TGF-beta 1 than VSMC from WKY rats. All these characteristics of SHR VSMC may contribute to the development of vascular hypertrophy in this strain.

Topics: Animals; Aorta, Thoracic; Cell Count; Cells, Cultured; Culture Media; Hypertension; Male; Muscle Development; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Transforming Growth Factor beta

We have examined the interactions between transforming growth factor-beta 1 (TGF-beta 1) and epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), or platelet-derived growth factor (PDGF) isoforms PDGF-AB and PDGF-BB on the proliferation of vascular smooth muscle cells isolated from the spontaneously hypertensive rat. TGF-beta 1 alone stimulated [3H]thymidine incorporation approximately twofold without a corresponding increase in cell number. In combination, TGF-beta 1 action was synergistic in further stimulating both DNA synthesis and cell proliferation 100-300% above the responses elicited by each growth factor. To gain further insight into the mechanism responsible for this potentiation, we examined the interaction between TGF-beta 1 and EGF. The synergistic interaction between TGF-beta 1 and EGF on DNA synthesis was independent of initial cell density. This effect of TGF-beta 1 was initiated early in the G1 phase of the cell cycle and did not appear to be mediated through the mobilization of Ca2+ or alterations in c-jun mRNA expression. However, in the presence of both TGF-beta 1 and EGF, there was a sustained elevation of c-myc mRNA levels over a 24-h period. These results suggest that TGF-beta 1 may interact with other growth factors in vivo to enhance their proliferative action on vascular smooth muscle of spontaneously hypertensive rats via mechanisms dependent on c-myc mRNA expression.

Topics: Animals; Cell Communication; Cell Cycle; Cell Division; DNA; Growth Substances; Hypertension; Male; Muscle, Smooth, Vascular; Proto-Oncogene Proteins c-myc; Rats; Rats, Inbred SHR; RNA, Messenger; Signal Transduction; Transforming Growth Factor beta

High potassium diets greatly reduce intimal and medial thickening in stroke-prone spontaneously hypertensive rats (SHRSP). In vascular smooth muscle cells, transforming growth factor-beta (TGF-beta) inhibits proliferation. To test whether high potassium diets decrease aortic thickening through TGF-beta, we measured TGF-beta-like activity in medium bathing aortas from rats fed either normal potassium or high potassium diets. Five-week-old SHRSP were fed 6% high NaCl diets containing either normal (0.5%) potassium (11 rats) or high (2.1%) potassium (14 rats) for 7 weeks. Aortas were freshly excised and perfused for 3 hours with tissue culture medium at ordinary arterial pressures. TGF-beta-like activity in the acid-activated perfusing medium was assessed using the growth inhibitory action on mink lung cells. Growth inhibition was assessed by [3H]thymidine incorporation. In the medium perfusing the outside of the aorta, the growth inhibitory rates were 2.5 times higher in high potassium SHRSP than in normal potassium SHRSP (-49% versus -20%, p less than 0.03). Antibodies to TGF-beta 1 and TGF-beta 2 were added to other aliquots and did not alter the results whatsoever. Thus, the difference in growth inhibition was not due to differences in TGF-beta. The high potassium aortas released 2.5 times more growth-inhibiting agents than the normal potassium aortas. The same pattern of growth inhibition was also seen using vascular smooth muscle cells rather than mink lung cells (r = +0.818, p less than 0.001, n = 13). The increased growth inhibition of high potassium aortas was not due to an increased release of heparin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antibodies; Aorta; Blood Pressure; Cell Division; Diet; Growth Inhibitors; Hypertension; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Perfusion; Potassium; Rats; Rats, Inbred SHR; Transforming Growth Factor beta

Previous investigations have demonstrated certain similarities in the cellular changes occurring in the arterial wall in response to hypertension and aging. We undertook the current studies to examine the expression of platelet-derived growth factor (PDGF) receptors and ligands and transforming growth factor-beta 1 (TGF-beta 1) in aorta and heart of spontaneously hypertensive rats (SHRs), Wistar-Kyoto (WKY) controls, and Wistar rats studied at ages ranging from 5 to 40 weeks. A progressive increase with age in aortic steady-state messenger RNA (mRNA) levels of the receptor for the B chain of PDGF (PDGF-r beta) was present in all three strains but was greatest in the SHR. The aortic expression of PDGF A or B ligands as well as of the PDGF-r alpha-receptor was not significantly influenced by age or blood pressure. In contrast, in the heart of the SHR and WKY rat, there was an age-related decrease in expression of both PDGF receptors and of the PDGF B chain. Hypertension and aging were associated with increases in steady-state mRNA for TGF-beta 1 in aorta, but in the heart, reductions again were observed. These studies indicate that both hypertension and aging increase the in vivo expression of PDGF-r beta and TGF-beta 1 in aortic tissue. Such changes might be functionally significant and provide autocrine or paracrine mechanisms for regulation of cellular growth in the arterial wall in response to these conditions. The findings also provide further support for the concept that hypertension accelerates the arterial changes associated with aging.

Topics: Aging; Animals; Aorta; Fibronectins; Gene Expression Regulation; Hypertension; Male; Myocardium; Platelet-Derived Growth Factor; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Receptors, Cell Surface; Receptors, Platelet-Derived Growth Factor; RNA, Messenger; Transforming Growth Factor beta

Topics: Animals; Aorta; Cerebrovascular Disorders; Disease Susceptibility; Hypertension; In Vitro Techniques; Male; Mink; Potassium; Rats; Rats, Inbred SHR; Transforming Growth Factor beta

Topics: Animals; Cell Division; Cells, Cultured; DNA; Epidermal Growth Factor; Hypertension; Muscle, Smooth, Vascular; Proto-Oncogene Proteins c-fos; Rats; Rats, Inbred SHR; RNA, Messenger; Transforming Growth Factor beta

This study was undertaken to determine if changes in fibronectin biosynthesis accompany the phenotypic changes that occur in aortic tissue following experimental hypertension. An in vitro procedure was developed to measure fibronectin synthesis in aortic rings obtained from normotensive or hypertensive rats. There was a three to sixfold increase in fibronectin biosynthesis by aortic rings taken from rats treated with deoxycorticosterone/salt for 7 and 21 d, the change being more pronounced at 21 d. In contrast, there was no major change at either time point in net incorporation into total protein. Studies comparing fibronectin biosynthesis in aortic rings from Wistar rats and spontaneously hypertensive rats at ages between 10 and 40 wk showed increased fibronectin biosynthesis in older animals of both strains, but only slight differences between strains. Studies using rats infused with angiotensin II showed a correlation between blood pressure elevation and increased aortic fibronectin biosynthesis. Western blot analysis of aortic extracts showed that the fibronectin content was increased in the hypertensive models. The in vitro procedure for measuring fibronectin biosynthesis appears to provide a reliable reflection of in vivo changes in fibronectin expression, and the methodology could prove useful for studying the factors influencing protein expression in vascular tissue.

Topics: Age Factors; Angiotensin II; Animals; Aorta; Fibronectins; Hypertension; In Vitro Techniques; Male; Protein Biosynthesis; Rats; Rats, Inbred SHR; RNA, Messenger; Transforming Growth Factor beta