transforming-growth-factor-beta and Kidney-Failure--Chronic

Nephropathy has become the most common reason for end-stage renal disease worldwide. The progression of end-stage renal disease occurs caused by decreased glomerular filtration rate, damage to capillaries in renal glomeruli or a higher risk of cardiovascular morbidity and mortality in diabetic patients. The involvement of mechanism in the development of nephropathy via generation of AGEs, the elevation of growth factors, altered hemodynamic and metabolic factors, inflammatory mediators, oxidative stress and dyslipidaemia. The prevalence of chronic kidney disease in India will rise from 3.7 million in 1990 to 7.63 million in 2020 becoming the main cause of mortality and morbidity. The pathogenesis of nephropathy mediates by various molecules that cause alterations in the structure and function of the kidney like growth factors, endothelins, transforming growth factor (TGF-β), and Angiotensin-converting enzymes (ACE), fibronectin and proinflammatory cytokines, mast cells and dyslipidemia. Growth factors like VEGF, IGFs, PDGF, EGFR and TGF-β contribute to excessive extracellular matrix accumulation, together with thickening of the glomerular and tubular basement membranes and an increase in the mesangial matrix, leading to glomerulosclerosis and tubulointerstitial fibrosis. Oxidative stress and inflammation factors like TNF-α, IL-1 and IL-6 are hypothesized to play a role in the development of pathological changes in nephropathy like renal hyperfiltration and hypertrophy, thickening of the glomerular basement membrane (GBM), glomerular lesion and tubulointerstitial fibrosis. Dyslipidemia is involved in the progression of nephropathy by impaired action of lipoprotein lipase, lecithincholesterol acyltransferase (LCAT) and cholesteryl ester transferase protein (CETP) resulting in the increased level of LDL-C, Triglyceride level and decrease HDL-C that enhance macrophage infiltration, excessive extracellular matrix production and accelerate inflammation with the development of proteinuria. Interruption in the RAS, oxidative stress and dyslipidemia have yielded much better results in terms of reno-protection and progression of nephropathy. In this review, we would focus on various factors that have been shown to contribute to renal injury in many experimental models of nephropathy.

Topics: Fibrosis; Humans; Inflammation; Interleukin-1; Interleukin-6; Kidney Failure, Chronic; Transforming Growth Factor beta

Renal fibrosis is the common pathological hallmark of progressive chronic kidney disease (CKD) with diverse aetiologies. Recent researches have highlighted the critical role of hypoxia during the development of renal fibrosis as a final common pathway in end-stage kidney disease (ESKD), which joints the scientist's attention recently to exploit the molecular mechanism underlying hypoxia-induced renal fibrogenesis. The scaring formation is a multilayered cellular response and involves the regulation of multiple hypoxia-inducible signalling pathways and complex interactive networks. Therefore, this review will focus on the signalling pathways involved in hypoxia-induced pathogenesis of interstitial fibrosis, including pathways mediated by HIF, TGF-β, Notch, PKC/ERK, PI3K/Akt, NF-κB, Ang II/ROS and microRNAs. Roles of molecules such as IL-6, IL-18, KIM-1 and ADO are also reviewed. A comprehensive understanding of the roles that these hypoxia-responsive signalling pathways and molecules play in the context of renal fibrosis will provide a foundation towards revealing the underlying mechanisms of progression of CKD and identifying novel therapeutic targets. In the future, promising new effective therapy against hypoxic effects may be successfully translated into the clinic to alleviate renal fibrosis and inhibit the progression of CKD.

Topics: Cell Hypoxia; Fibrosis; Humans; Kidney; Kidney Failure, Chronic; MicroRNAs; NF-kappa B; Receptors, Notch; Signal Transduction; Transforming Growth Factor beta

Diabetic nephropathy is rapidly becoming the major cause of end-stage renal disease and cardiovascular mortality worldwide. Standard of care therapies include strict glycemic control and blockade of the renin-angiotensin-aldosterone axis. While these treatments slow progression of diabetic nephropathy, they do not arrest or reverse it. Newer therapies targeting multiple molecular pathways involved in renal inflammation, fibrosis, and oxidative stress have shown promise in animal models. Subsequently, many of these agents have been investigated in clinical human trials with mixed results. In this review, we will discuss recent findings of novel agents used in the treatment of diabetic nephropathy.

Topics: Animals; Diabetic Nephropathies; Humans; Janus Kinases; Kidney Failure, Chronic; Oxidative Stress; Signal Transduction; STAT Transcription Factors; Transforming Growth Factor beta

The concept of reversing chronic kidney disease (CKD) has been intensively researched over the past decade. Indeed, as the prevalence of end-stage renal disease is constantly on the rise, the lack of established antifibrotic therapies is a considerable unmet need in clinical practice. Now, the possibility of effective antifibrotic treatment has been established in experimental models of CKD and multiple antifibrotic compounds-in kidney disease, as well as in fibrotic diseases of the skin, liver and lung-are being assessed in clinical trials. These strategies target various components of the fibrotic pathway, from signalling molecules that include transforming growth factor-β, phosphatidylinositide 3-kinase and chemokines to microRNAs. Here, we discuss therapeutic concepts to inhibit or even reverse chronic kidney injury and review the leading candidate antifibrotic drugs to be introduced to clinical use.

Topics: Anti-Inflammatory Agents; Bone Morphogenetic Protein 7; Connective Tissue Growth Factor; Disease Progression; Endothelin-1; Epigenesis, Genetic; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Microcirculation; Phosphodiesterase Inhibitors; Pyridones; Transforming Growth Factor beta

Nephropathy is one of the major complications of diabetes which further directs to end stage renal disease. Extensive work has been done to find out the mechanisms involved in pathogenesis of the DN. Now, many researchers have been convinced that almost all of the molecular mediators and intracellular signaling pathways involved in progression of diabetic nephropathy have involvement in transforming growth factor beta (TGF- β) at some stage. In DN, hyperglycemia causes increase in the expression of TGF- β genes, TGF- β proteins and their receptors. Increased glucose level mediates these effects through activation of polyol pathway, protein kinase C pathway, hexosamine pathway, increases advanced glycation end products (AGE) and increases oxidative stress. Hyperglycemia also activates the TGF- β via activation of glucose transporters (GLUT), angiotensine II and platelet derived growth factor (PDGF). Activated TGF-β further leads to glomerular basement membrane (GBM) thickening and glomerulosclerosis through activation of connective tissue growth factor (CDGF) and vascular endothelial growth factor (VEGF). We have discussed the progression of hyperglycemia to DN via TGF- β, whose schematic presentation may serve as an effective way to understand the mechanisms and to find out an effective way for the management of diabetic nephropathy.

Topics: Diabetic Nephropathies; Disease Progression; Glucose Transporter Type 5; Glycation End Products, Advanced; Humans; Hyperglycemia; Intercellular Signaling Peptides and Proteins; Kidney Failure, Chronic; Oxidative Stress; Protein Kinase C; Receptors, Platelet-Derived Growth Factor; Signal Transduction; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Diabetes is the single largest contributor to the growing prevalence of chronic kidney disease (CKD), and episodes of acute kidney injury (AKI) increase the risk of advanced CKD in diabetic patients. Here we discuss whether the pathophysiological changes that occur in the tubular system of the diabetic kidney affect the intrinsic susceptibility to AKI. There is abundant data showing that drug-induced nephrotoxicity is attenuated in rodents with experimental diabetes mellitus, and some mechanistic explanations have been provided, in particular in response to aminoglycosides. Besides downregulation in proximal tubular megalin, which mediates the aminoglycoside uptake in proximal tubules, a role for hyperglycemia-induced activation of regenerative mechanisms has been proposed. The available clinical data, however, indicates that diabetes is a risk factor for AKI, including aminoglycoside nephrotoxicity. While much needs to be learned about this disconnect, the isolated induction of diabetes in otherwise healthy young adult rodents may simply not fully mimic the influence that diabetes exerts in the setting of a critically ill and often elderly patient. We speculate that diabetic tubular growth and the associated molecular signature (including upregulation of TGF-β, senescence, and inflammation) set up the development of diabetic nephropathy and renal failure in part by increasing the susceptibility to AKI, which further promotes hypoxia and apoptosis. Considering the strong association between AKI episodes and the cumulative risk of developing advanced CKD in diabetes, strategies that reduce AKI in these patients are expected to help reduce the growing burden of end-stage renal disease.

Topics: Acute Kidney Injury; Age Factors; Aminoglycosides; Animals; Anti-Bacterial Agents; Cell Cycle; Cellular Senescence; Critical Illness; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Disease Susceptibility; Fibrosis; Gene Expression Profiling; Glomerular Filtration Rate; Humans; Hypertrophy; Inflammation; Kidney Failure, Chronic; Kidney Tubules, Proximal; Meta-Analysis as Topic; Observational Studies as Topic; Risk Factors; Sodium Chloride, Dietary; Transforming Growth Factor beta

Transforming growth factor beta (TGF-β) has been recognized as an important mediator in the genesis of chronic kidney diseases (CKD), which are characterized by the accumulation of extracellular matrix (ECM) components in the glomeruli (glomerular fibrosis, glomerulosclerosis) and the tubular interstitium (tubulointerstitial fibrosis). Glomerulosclerosis is a major cause of glomerular filtration rate reduction in CKD and all three major glomerular cell types (podocytes or visceral epithelial cells, mesangial cells and endothelial cells) participate in the fibrotic process. TGF-β induces (1) podocytopenia caused by podocyte apoptosis and detachment from the glomerular basement membrane; (2) mesangial expansion caused by mesangial cell hypertrophy, proliferation (and eventually apoptosis) and ECM synthesis; (3) endothelial to mesenchymal transition giving rise to glomerular myofibroblasts, a major source of ECM. TGF-β has been shown to mediate several key tubular pathological events during CKD progression, namely fibroblast proliferation, epithelial to mesenchymal transition, tubular and fibroblast ECM production and epithelial cell death leading to tubular cell deletion and interstitial fibrosis. In this review, we re-examine the mechanisms involved in glomerulosclerosis and tubulointerstitial fibrosis and the way that TGF-β participates in renal fibrosis, renal parenchyma degeneration and loss of function associated with CKD.

Topics: Extracellular Matrix; Fibrosis; Humans; Inflammation; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Tubules; Podocytes; Transforming Growth Factor beta

Fibrosis plays a major role in the pathogenesis of progressive chronic kidney disease (CKD). The inhibition of the renin-angiotensin system, which promotes fibrosis, has become the standard of care in the treatment of patients with CKD. The use of alternative agents capable of blocking the actions of profibrotic cytokines such as transforming growth factor-beta (TGF-β) is also an important strategy that is in its early stages of development. An example of such a drug is AST-120, a charcoal compound that ultimately inhibits the synthesis of TGF-β in the kidney. The inhibition is mediated by blocking the intestinal absorption of tryptophan-derived indole by AST-120. This reduces the hepatic conversion of indole to indoxyl sulfate (IS). IS stimulates the production of TGF-β in the renal parenchyma, and lowering the level of IS with AST-120 appears to slow progression of CKD. The status of recent trials examining the safety and efficacy of AST-120 has been described, including a multicenter, randomized, placebo-controlled, phase III trial of approximately 2,000 subjects being conducted to gain approval of this drug by the U.S. Food and Drug Administration.

Topics: Adsorption; Carbon; Disease Progression; Fibrosis; Humans; Indican; Intestinal Absorption; Kidney Failure, Chronic; Microspheres; Oxides; Renin-Angiotensin System; Transforming Growth Factor beta; Tryptophan

Tubulointerstitial fibrosis mediates the development of end-stage renal disease from renal injuries of all etiologies and is considered an important predictor of renal survival. Transforming growth factor-β (TGF-β) is one of the most important growth factors that promotes tubulointerstitial fibrosis, but the mechanisms whereby this occurs are not well defined. This is because TGF-β has pleiotropic effects that depend on the target cell type. This review discusses how TGF-β signaling in each of the relevant cell types (eg, tubular epithelium, fibroblasts) may contribute to tubulointerstitial fibrosis progression and suggests ways in which future research can improve our understanding of TGF-β-mediated tubulointerstitial fibrosis.

Topics: Acute Kidney Injury; Endothelium; Epithelium; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Kidney; Kidney Failure, Chronic; Kidney Tubules; Renal Insufficiency, Chronic; Signal Transduction; Transforming Growth Factor beta

Renal tubulo-interstitial fibrosis is a non-specific process, representing the final common pathway for all kidney diseases, irrespective of their initial cause, histological injury, or etiology, leading to gradual expansion of the fibrotic mass which destroys the normal structure of the tissue and results in organ dysfunction and, ultimately, in end-stage organ failure. Proteomic studies of the fibrotic pathophysiological mechanisms have been performed in cell cultures, animal models and human tissues, addressing some of the key issues. This article will review proteomic contribution to the raising current knowledge on renal fibrosis biology and also mention seminal open questions to which proteomic techniques and proteomists could fruitfully contribute.

Topics: Animals; Blood Glucose; Cyclosporine; Diabetic Nephropathies; Fibrosis; Glomerulonephritis; Humans; Hypoxia; Kidney; Kidney Diseases; Kidney Failure, Chronic; Proteomics; Transforming Growth Factor beta

In this review,firstly,it has been discussed the mechanisms of Chinese herbal medicine ameliorating glomerulosclerosis and renal interstitial fibrosis during the progression of chronic renal failure (CRF) by improving glomerular hemodynamics turbulence, podocyte injury, transforming growth factor (TGF)-beta over-expression, hyperlipidemia, macrophage infiltration, tubular epithelial myofibroblast transdifferentiation, and nephrotoxicity of proteinuria. Secondly,it has been reported the clinical effects of Chinese herbal medicine improving renal function and some clinical complications in the patients with progressive CRF through various treatments including oral administration or coloclysis of Chinese herbal medicine, oral administration combined with coloclysis of Chinese herbal medicine, and colonic dialysis combined with coloclysis of Chinese herbal medicine. Finally,it has been reviewed the beneficial influences of Chinese herbal medicine on metabolic dysequilibrium of calcium and phosphonium, microinflammatory state, and uremic toxins in patients with uremia.

Topics: Animals; Drugs, Chinese Herbal; Humans; Kidney; Kidney Failure, Chronic; Transforming Growth Factor beta

Peritoneal membrane changes over time in long-term peritoneal dialysis (PD) patients lead to dialysis failure and increased morbidity as well as mortality. Bio-incompatable PD solution, peritonitis, and uremia are hypothesized in causing membrane damage. Fibrous organization and angiogenesis of peritoneum are crucial morphological alterations which can diminish the efficacy of exchange and cause ultrafiltration failure. Pathophysiologic mechanisms of membrane damage have been extensively studied to innovate therapeutic strategies. One of the potential mechanisms is a presence of local renin-angiotensin-aldosterone system (RAAS) by which injured peritoneal mesothelial cell-derived angiotensin-II (AII) causes activations in TGF-beta, VEGF expression, and epithelial-to-mesenchymal transition (EMT) which contributes to extracellular matrix accumulation and neoangiogenesis in submesothelial tissues. Clinical evidence of RAAS blockade on human peritoneal membrane remains under investigation and is still inconclusive but relevant data seem to demonstrate its benefit on membrane preservation. Longitudinal effect of RAAS blockade on membrane structural, functional, and clinical relationships and strategies to use angiotensin converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), aldosterone antagonist, and direct renin inhibitor are an interesting field to be explored.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Epithelial Cells; Humans; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Peritoneal Dialysis; Peritoneum; Renin; Renin-Angiotensin System; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Vasoconstrictor Agents

The past 2 decades have brought rapid advances in treatment options for chronic kidney disease; however, even with the best treatment, the decline of renal function and progression to end-stage renal disease (ESRD) continues in a significant number of patients. The prognosis of patients with diabetes and ESRD is grim, with < 50% of patients surviving beyond 5 years after diagnosis. Therefore, early recognition and optimal use of available interventions are essential, and research into newer therapeutic targets is needed. This article will review recent advances in our understanding of renal pathophysiology, summarize the evidence to date supporting current treatment options for diabetic nephropathy, and highlight new options that lie on the horizon for the treatment of diabetic kidney disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Glycation End Products, Advanced; Humans; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Oxidative Stress; Renin-Angiotensin System; Transforming Growth Factor beta

Ultrafiltration failure (UFF) continues to be a major complication of peritoneal dialysis (PD), particularly long-term PD. Continuous exposure to bioincompatible PD solutions causes inflammation of the peritoneal membrane, which progressively undergoes fibrosis and angiogenesis and, ultimately, UFF. There is emerging evidence that epithelial-mesenchymal transition (EMT) of peritoneal mesothelial cells (MCs) may play an important role in the failure of peritoneal membrane function. Submesothelial myofibroblasts originating from MCs through EMT and from activated resident fibroblasts participate in inflammatory responses, extracellular matrix accumulation, and angiogenesis. High glucose and glucose degradation products from PD solutions are responsible for production of transforming growth factor beta (TGFbeta) and vascular endothelial growth factor (VEGF) by MCs, which induce EMT. Leptin and receptor for advanced glycation end-products (AGEs) augment myofibroblastic conversion through the TGFbeta signaling system. A reduction in osmotic conductance in addition to increased solute transport causes UFF. This situation may be caused by loss of aquaporin (AQP) function and formation of the submesothelial fibrotic layer. During PD, AQP1 plays an essential role in water permeability and ultrafiltration (UF), modulating processes such as endothelial permeability and angiogenesis. During a hypertonic dwell, AQP1 mediates 50% of UF. Insufficient AQP1 function may be causative for inadequate UFF. A significant amount of evidence from animal studies now exists to show that mast cells communicate with fibroblasts and are implicated in fibrogenesis, angiogenesis, and UFF. However, it is not confirmed in human studies that mast cells contribute to the fibrosis seen in the peritoneum of PD patients. The patterns of UFF in PD patients depend on duration of treatment. Inherently high small-solute transport status is associated with hypoalbuminemia and a greater comorbidity index. However, most of the variability in peritoneal transport remains unexplained, pointing to the potential role of genetic factors. Gene polymorphisms associated with peritoneal membrane transport have been identified. Recent studies have shown that VEGF, interleukin-6, endothelial NO synthase, AGE receptor, and RAS gene polymorphisms are associated with transport properties in PD patients. Current insights into the mechanisms of UFF will provide rationales for new therapeutic strategies.

Topics: Animals; Aquaporin 1; Biological Transport; Cell Membrane Permeability; Dialysis Solutions; Epithelial Cells; Humans; Kidney Failure, Chronic; Peritoneal Dialysis; Peritoneum; Transforming Growth Factor beta; Treatment Failure; Vascular Endothelial Growth Factor A

Transforming growth factor (TGF)-beta is a central stimulus of the events leading to chronic progressive kidney disease, having been implicated in the regulation of cell proliferation, hypertrophy, apoptosis and fibrogenesis. The fact that it mediates these varied events suggests that multiple mechanisms play a role in determining the outcome of TGF-beta signaling. Regulation begins with the availability and activation of TGF-beta and continues through receptor expression and localization, control of the TGF-beta family-specific Smad signaling proteins, and interaction of the Smads with multiple signaling pathways extending into the nucleus. Studies of these mechanisms in kidney cells and in whole-animal experimental models, reviewed here, are beginning to provide insight into the role of TGF-beta in the pathogenesis of renal dysfunction and its potential treatment.

Topics: Humans; Kidney; Kidney Failure, Chronic; Protein Binding; Signal Transduction; Transforming Growth Factor beta

Increasing evidence shows that transforming growth factor-beta TGF-beta1 (TGF-beta1) is upregulated and plays a diverse role in renal fibrosis by stimulating extracellular matrix (ECM) production, while inhibiting renal inflammation. Recent studies have identified that TGF-beta1, once activated, signals through its downstream signaling pathway to exert its biological effects. It is now well accepted that TGF-beta regulates fibrosis positively by receptor-associated Smads including Smad2 and Smad3, but negatively by an inhibitory Smad, called Smad7. We and other investigators have shown that gene transfer of Smad7 is able to inhibit renal fibrosis in a number of experimental models of chronic kidney diseases, including obstructive nephropathy, remnant kidney disease, and autoimmune crescentic glomerulonephritis. Blockade of Smad2/3 activation is a major mechanism by which overexpression of Smad7 inhibits renal scarring. Furthermore, our recent findings also demonstrate that Smad7 plays a critical role in anti-inflammation in chronic kidney diseases by blocking the NF.kappaB-dependent inflammatory pathway. Thus, Smad7 has a unique role in both anti-renal fibrosis and inflammation. These findings also indicate that targeting the TGF-beta/Smad signaling pathway by overexpressing Smad7 may provide a novel, specific, and effective therapy for chronic kidney diseases.

Topics: Epithelial Cells; Fibrosis; Humans; Inflammation; Kidney Diseases; Kidney Failure, Chronic; Kidney Tubules; NF-kappa B; Signal Transduction; Smad7 Protein; Transforming Growth Factor beta

Progression of diabetic nephropathy (DN) is manifested by gradual scarring of both the renal glomerulus and tubulointerstitial region. Over the past several years, the general understanding of the pathogenic factors that lead to renal fibrosis in DN has expanded considerably. In this review, some of the important factors that appear to be involved in driving this fibrosing process are discussed, with special emphasis on newer findings and insights. It is now clear that multiple cell types in the kidney contribute to progressive fibrosis in DN. New concepts about bradykinin, TGF-beta and eNOS signaling as well as JAK/STAT activation and the central role of inflammation in both glomerular and tubulointerstitial fibrosis are discussed.

Topics: Animals; Bradykinin B2 Receptor Antagonists; Diabetic Nephropathies; Disease Progression; Eicosanoids; Fibrosis; Humans; Inflammation; Janus Kinases; Kidney; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Tubules; Lipid Metabolism; MicroRNAs; Nitric Oxide Synthase Type III; Plasminogen Activator Inhibitor 1; Protein C; Sclerosis; STAT Transcription Factors; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

In the last decade, the nephrology community has focused its attention on the main cause of morbidity and mortality in chronic renal failure patients: cardiovascular disease. In addition, recent studies pointed out that vascular calcification (VC) is a major cause of cardiovascular disease in the dialysis population. Interestingly, the pathogenesis of VC and soft tissue calcification in chronic kidney disease (CKD) has been extensively investigated. Nowadays we know that VC is associated not only with passive calcium phosphate deposition, but also with an active, cell-mediated process. To better understand the pathogenesis of VC in CKD, numerous regulatory proteins have been studied, because of their ability to inhibit mineral deposition in the vessels. We here examine the state of the art of those substances recognized as regulatory key factors in preventing VC in uremic conditions, such as fetuin A (alpha2-Heremans-Schmid glycoprotein), matrix gamma-carboxyglutamic acid protein, pyrophosphate, osteoprotegerin and bone morphogenetic protein. We conclude that at present it is too early to introduce these novel markers into clinical practice.

Topics: 1-Carboxyglutamic Acid; alpha-Fetoproteins; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcinosis; Diphosphates; Humans; Kidney Failure, Chronic; Models, Biological; Osteoprotegerin; Risk Factors; Transforming Growth Factor beta; Uremia; Vascular Diseases

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

Epithelial-mesenchymal transition (EMT) plays an important role in embryogenesis and organ formation. Over the last 10-15 years it has been established that EMT is a significant mechanism of tumor progression and metastasis formation and also of progressive tissue fibrosis in the kidney, liver and lung. EMT seen in these diverse physiological and pathophysiological contexts shares a number of stages and modules, but also carries distinct, context specific characteristics. EMT in tissue fibrosis is a form of reverse embryogenesis, when highly specialized epithelial cells in the specific organs will respond to injury with loosing their epithelial characteristics and functions and regaining characteristics of the cells from which they originated. EMT in the context of tissue fibrosis can be induced by different forms of injury or a set of humoral factors. The process is regulated by a complex balance of humoral and microenvironmental stimuli, in which cell-cell contacts and interaction of the transitioning cell with the extracellular matrix components is very important. Intense research in this exciting field yielded good understanding of many of the details of this fascinating process, although numerous questions still await proper answers. There is indication that understanding of the molecular mechanisms underlying "fibrotic" EMT may lead to the design of specific and effective therapeutic measures for progressive tissue fibrosis.

Topics: Adherens Junctions; Animals; Cell Differentiation; Epithelial Cells; Fibrosis; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Kidney Tubules; Mesoderm; Tight Junctions; Transforming Growth Factor beta

The Medical Subject Headings (MeSH) thesaurus used by the National Library of Medicine defines logistic regression models as "statistical models which describe the relationship between a qualitative dependent variable (that is, one which can take only certain discrete values, such as the presence or absence of a disease) and an independent variable." Logistic regression models are used to study effects of predictor variables on categorical outcomes and normally the outcome is binary, such as presence or absence of disease (e.g., non-Hodgkin's lymphoma), in which case the model is called a binary logistic model. When there are multiple predictors (e.g., risk factors and treatments) the model is referred to as a multiple or multivariable logistic regression model and is one of the most frequently used statistical model in medical journals. In this chapter, we examine both simple and multiple binary logistic regression models and present related issues, including interaction, categorical predictor variables, continuous predictor variables, and goodness of fit.

Topics: Data Interpretation, Statistical; Humans; Kidney Failure, Chronic; Liver Transplantation; Logistic Models; Models, Biological; Odds Ratio; Polymorphism, Genetic; Transforming Growth Factor beta

Topics: Animals; Cell Differentiation; Cell Division; Fibroblasts; Fibrosis; Glomerular Mesangium; Hepatocyte Growth Factor; Humans; Kidney; Kidney Failure, Chronic; Kidney Tubules; Transforming Growth Factor beta

Cachexia causes weight loss and increased mortality. It affects more than 5 million persons in the United States. Other causes of weight loss include anorexia, sarcopenia, and dehydration. The pathophysiology of cachexia is reviewed in this article. The major cause appears to be cytokine excess. Other potential mediators include testosterone and insulin-like growth factor I deficiency, excess myostatin, and excess glucocorticoids. Numerous diseases can result in cachexia, each by a slightly different mechanism. Both nutritional support and orexigenic agents play a role in the management of cachexia.

Topics: Aging; Anorexia; Arthritis, Rheumatoid; Cachexia; Chronic Disease; Cytokines; Glucocorticoids; HIV Wasting Syndrome; Humans; Insulin-Like Growth Factor I; Kidney Failure, Chronic; Myostatin; Neoplasms; Pulmonary Disease, Chronic Obstructive; Testosterone; Transforming Growth Factor beta; Weight Loss

Glomerulosclerosis, interstitial fibrosis, and tubular atrophy occur with end-stage kidney failure, irrespective of the primary etiology. The transforming growth factor-beta (TGF-beta) is a key factor in these alterations either directly, by stimulating synthesis of extracellular matrix components and reducing collagenase production, or indirectly through other profibrogenic factors such as connective tissue growth factor (CTGF). TGF-beta is important for the proliferation of intrarenal fibroblasts and the epithelial-mesenchymal transition through which tubular cells become fibroblasts. Although several factors induce TGF-beta expression in the kidney, one very interesting aspect is the link between the renin-angiotensin-aldosterone (Aldo) system (RAAS) and TGF-beta. Angiotensin II (ANG II) stimulates TGF-beta expression in the kidney by various mechanisms and upregulates receptors for TGF-beta. ANG II can directly phosphorylate Smads without inducing TGF-beta. Recent data provide compelling evidence that other components of the RAAS including ANG III, renin, and Aldo also activate the TGF-beta system. As direct modulation of the TGF-beta system is not yet feasible in humans, angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 (AT1)-receptor blockers are currently the most potential drugs to interfere with this ANG II-mediated TGF-beta expression. This review highlights some current aspects of the interaction between the RAAS and the TGF-beta axis.

Topics: Angiotensin II; Humans; Kidney; Kidney Failure, Chronic; Renin-Angiotensin System; Signal Transduction; Transforming Growth Factor beta

Renal fibrosis is an evolutive process frequently leading to end stage renal failure. Several studies have demonstrated the dominant and mutually antagonistic roles of two proteins from the transforming growth factor superfamily. BMP-7 has a protective effect on the kidney, by decreasing apoptosis, maintaining and restoring the epithelial phenotype and dysplaying anti-fibrotic activity. The mechanisms through which TGF beta 1 favours fibrosis are still unclear, although most of its activity appears to be due to antagonism of the effects of BMP-7. Animal studies are very encouraging, as exogenous BMP-7 has allowed stabilisation and even regression of renal fibrosis with a concomitant stabilisation or improvement of renal function. The therapeutic implications of these findings are promising.

Topics: Bone Morphogenetic Proteins; Diabetic Nephropathies; Fibrosis; Humans; Kidney Failure, Chronic; Transforming Growth Factor beta; Ureteral Obstruction

Topics: Animals; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Gene Expression Regulation, Developmental; Humans; Kidney; Kidney Failure, Chronic; Transforming Growth Factor beta

Secondary hyperparathyroidism (SHP) is a frequent complication of dialysis patients. In this second article we will analyze the new vitamin D analogs, capable of decreasing parathyroid hormone (PTH) levels with a lower effect on intestinal calcium and phosphorus absorption. Among other advantages described in the experimental setting, paricalcitol shows a survival benefit in dialysis patients as compared to calcitriol, at least in retrospective studies, and thus it became our first-line vitamin D derivative. Calcimimetics are unique since they decrease PTH levels without increasing serum calcium and phosphorus. Actually, calcium and phosphorus decrease in a significant number of patients. These drugs will soon be authorized in Spain, and we describe the better achievement of K/DOQI guidelines as well as other beneficial effects observed in the experimental animal with them. Finally, we mention the potential benefit of mild metabolic acidosis, the use of bisphosphonates, the role of bone morphogenetic protein BMP-7, and the use of teriparatide. The future treatment of SHP will probably require the independent management of calcium, phosphorus, vitamin D and PTH. Thus, low-dose combined treatments with selective drugs may prove more effective than sequential therapies.

Topics: Animals; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcium; Cinacalcet; Diphosphonates; Drug Therapy, Combination; Ergocalciferols; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Naphthalenes; Parathyroid Hormone; Phosphorus; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Renal Dialysis; Retrospective Studies; Teriparatide; Transforming Growth Factor beta; Vitamin D

Topics: Administration, Oral; Adsorption; Animals; Carbon; Clinical Trials as Topic; Contraindications; Humans; Indican; Kidney Failure, Chronic; Kidney Tubules, Proximal; Organic Anion Transporters; Oxides; Transforming Growth Factor beta

When last reviewed, bone morphogenetic protein 7 was presented as a potential new renal therapeutic agent, with multiple efficacies in chronic kidney disease. The object of this review is to describe progress from many sources since then in support or denial of the hypothesis.. Bone morphogenetic protein 7 has been shown to be an effective defence in several forms of chronic kidney disease in animal models, and its mechanisms of action have begun to be elucidated. Bone morphogenetic protein 7 inhibits tubular epithelial cell de-differentiation, mesenchymal transformation and apoptosis stimulated by various renal injuries. Bone morphogenetic protein 7 preserves glomerular integrity and inhibits injury-mediated mesangial matrix accumulation. In renal osteodystrophy, bone morphogenetic protein 7 affects osteoblast morphology and number, eliminates peritrabecular fibrosis, decreases bone resorption, and increases bone formation in secondary hyperparathyroidism. Bone morphogenetic protein 7 restores normal rates of bone formation in the adynamic bone disorder. Bone morphogenetic protein 7 is broadly efficacious in renal osteodystrophy, and importantly increases the skeletal deposition of ingested phosphorus and calcium, improving ion homeostasis in chronic kidney disease. Bone morphogenetic protein 7 was shown to prevent vascular calcification in a model of chronic kidney disease associated with the restoration of osteocalcin expression to normal tissue-restricted sites.. Bone morphogenetic protein 7 may be a powerful new therapeutic agent for chronic kidney disease, with the novel attribute of not only treating the kidney disease itself, but also directly inhibiting some of the most important complications of the disease state.

Topics: Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcinosis; Chronic Kidney Disease-Mineral and Bone Disorder; Diabetic Nephropathies; Fibrosis; Humans; Kidney Diseases; Kidney Failure, Chronic; Lupus Nephritis; Nephritis, Hereditary; Transforming Growth Factor beta; Vascular Diseases

Progression of chronic nephropathies still represents a major challenge for clinical nephrologists. Specific therapies that prevent patients from requiring dialysis or transplantation are still not available. However, recent experimental studies have demonstrated that regression of advanced lesions in the kidney can be achieved. This review summarizes the recent therapeutic advances using experimental models that might translate into novel human therapies to prevent, or significantly delay, requirement of renal replacement therapy.

Topics: Hepatocyte Growth Factor; Humans; Kidney Failure, Chronic; Regeneration; Renin-Angiotensin System; Transforming Growth Factor beta

Topics: Cell Differentiation; Epithelial Cells; Fibroblasts; Fibrosis; Humans; Kidney; Kidney Failure, Chronic; Mesenchymal Stem Cells; Transforming Growth Factor beta

Diabetic nephropathy is continuing to rise in incidence, despite awareness of tight glycemic control and blood pressure. The identification that matrix accumulation is driven by transforming growth factor-beta (TGF-beta) has led to a concerted effort to apply antifibrotic strategies for this disorder. Recent studies have not only demonstrated the beneficial effects of blocking TGF-beta on matrix accumulation but have also found that blocking TGF-beta may have important hemodynamic effects that are relevant to diabetic complications. In this article, we review the latest knowledge regarding the role of TGF-beta in diabetic kidney disease and discuss available and novel therapeutic approaches. The role of a novel antifibrotic drug, pirfenidone, may have important clinical relevance to diabetic nephropathy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Diabetic Nephropathies; Disease Models, Animal; Humans; Kidney Failure, Chronic; Pyridones; Transforming Growth Factor beta

Tubulointerstitial fibrosis is a hallmark feature of chronic renal injury. Specific therapies to control the progression of renal fibrosis towards end-stage renal failure are still limited. Transforming growth factor-beta1 (TGF-beta1) has been identified as a major mediator of renal fibrosis. Recent reports have suggested that Bone Morphogenic Protein-7 (BMP-7), another member of the TGF-beta superfamily, accelerates repair of acute renal injury and ameliorates progression of chronic renal fibrosis in a variety of animal models. Interestingly, BMP-7, an endogenous molecule which is present in the normal kidney, vastly decreases its expression during renal injury. Although, the mechanism of BMP-7 action in the kidney is not yet fully understood, the idea of an endogenous molecule with reno-protective function is intriguing.

Topics: Animals; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Fibrosis; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Mice; Transforming Growth Factor beta

Risk factors for progression of kidney disease include hypertension, proteinuria, male sex, obesity, diabetes mellitus, hyperlipidemia, smoking, high-protein diets, phosphate retention, and metabolic acidosis. Angiotensin II production upregulates the expression of transforming growth factor-beta1, tumor necrosis factor-alpha, nuclear factor-kappaB, and several adhesion molecules and chemoattractants. In addition to angiotensin, other vasoactive compounds, such as thromboxane A(2), endothelin, and prostaglandins, are upregulated. Treatment with one of several growth factors may ameliorate the progression of kidney disease: insulin-like growth factor-1, hepatocyte growth factor, and bone morphogenetic protein-7.

Topics: Angiotensin II; Animals; Disease Progression; Growth Substances; Humans; Kidney Failure, Chronic; NF-kappa B; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Topics: Animals; Disease Models, Animal; Fibrosis; Humans; In Vitro Techniques; Kidney Diseases; Kidney Failure, Chronic; Mice; Rats; Thrombospondin 1; Transforming Growth Factor beta

We now know that the rate of progression of diabetic nephropathy, like all progressive renal disease, correlates with the degree of corticointerstitial fibrosis. Therefore, much interest has focused on the contribution of the resident cells in the renal cortex to this process. This article reviews the evidence that the epithelial cells of the proximal tubule are major players in orchestrating events in the corticointerstitium in diabetic nephropathy. More specifically, it addresses their role in extracellular matrix turnover, generation of cytokines, and recruitment of inflammatory cells, as well as examining the concept that they are the source of the interstitial myofibroblasts, which are the principal mediators of the fibrotic process.

Topics: Animals; Diabetic Nephropathies; Humans; Kidney Cortex; Kidney Failure, Chronic; Kidney Tubules, Proximal; Transforming Growth Factor beta

The inhibition of angiotensin II through angiotensin converting enzyme inhibitors or angiotensin receptor blockers has become the foundation of medical treatment of progressive chronic renal disease. Although these drugs provide a significant improvement over earlier treatments, they only slow the progression of renal disease, implying the need for additional drugs that could be combined with antiangiotensin treatment. Potentially valuable novel drug targets include downstream mediators of angiotensin II such as transforming growth factor-b, plasminogen activator inhibitor-1, and endothelin-1. In addition, recent evidence points to aldosterone as a major player in progressive renal disease, indicating that multiple points of the renin-angiotensin-aldosterone system might have to be targeted. This paper reviews the experimental and clinical evidence indicating that targeting these cytokines and hormones could provide additional benefits to antiangiotensin treatment in chronic renal disease.

Topics: Aldosterone; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Endothelins; Humans; Kidney Failure, Chronic; Plasminogen Activator Inhibitor 1; Receptors, Angiotensin; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-beta) superfamily members are multifunctional growth factors that play pivotal roles in development and tissue homeostasis. Recent studies have underscored the importance of TGF-beta in regulation of cell proliferation and extracellular matrix synthesis and deposition. TGF-beta signaling is initiated by ligand binding to a membrane-associated receptor complex that has serine/threonine kinase activity. This receptor complex phosphorylates specific Smad proteins, which then transduce the ligand-activated signal to the nucleus. Smad complexes regulate target gene transcription either by directly binding DNA sequences, or by complexing with other transcription factors or co-activators. There is extensive crosstalk between the TGF-beta signaling pathway and other signaling systems, including the mitogen-activated protein kinase pathways. The importance of TGF-beta in regulation of cell growth has been emphasized by recent observations that mutations of critical elements of the TGF-beta signaling system are associated with tumor progression in patients with many different types of epithelial neoplasms. TGF-beta has emerged as a predominant mediator of extracellular matrix production and deposition in progressive renal disease and in other forms of chronic tissue injury. In this overview, recent advances in our understanding of TGF-beta signaling, cell cycle regulation by TGF-beta, and the role of TGF-beta in progressive renal injury are highlighted.

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

During the last decade, therapeutic measures based on inhibitors of the angiotensin I converting enzyme have proved to have some efficacy in the prevention of renal fibrosis. This review is devoted to new anti-fibrotic strategies aimed at inhibiting reabsorption by proximal tubule cells of filtrated proteins, preventing transdifferentiation of proximal tubule cells, inhibiting the pro-inflammatory effects of angiotensin II and endothelin, blocking TGF beta, and limiting renal ischaemia. Furthermore, experimental models and clinical reports have shown that renal fibrosis could regress, which has important therapeutic implications. The design of new preventive and curative treatments should be accompanied by the identification of urinary and serum markers of the various stages of renal fibrosis.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Endothelins; Humans; Ischemia; Kidney; Kidney Failure, Chronic; Kidney Tubules, Proximal; Mice; Models, Animal; Proteinuria; Rats; Sclerosis; Transforming Growth Factor beta

The molecular cloning of many bone morphogenetic proteins (BMP)-encoding genes and their identification as transforming growth factor-beta (TGF-beta) relatives enhanced the interest in these molecules and allowed expression and functional studies to be performed.. Rats with ureteral obstruction were distributed into four groups. Group 1 received vehicle, group 2 received enalapril 12.5 mg/kg body wt/day, group 3 received 50 or 300 microg/kg body wt BMP-7, and group 4 received both enalapril and the high dose of BMP-7. We also studied the effects of BMP-7 administration in a model streptozocin-induced diabetes.. Treatment with BMP-7 in rats with ureteral obstruction of 3 days duration and subsequent release indicated that this compound decreases interstitial volume and accelerates the return of renal function. After 16 weeks of diabetes, the rats were treated with BMP-7. The administration of BMP-7 partially reversed renal hypertrophy, restored GFR to normal, and decreased proteinuria.. These studies indicate that administration of BMP-7 maintains and restores renal function and structure in animals with ureteral obstruction and diabetic nephropathy.

Topics: Animals; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Disease Progression; Kidney Failure, Chronic; Rats; Time Factors; Transforming Growth Factor beta

Current investigation of the pathogenesis of tubulointerstitial injury indicates that both interstitial fibroblasts and renal tubular epithelial cells promote extracellular matrix accumulation. Moreover, two peptides--TGF-beta and angiotensin II--produced locally or delivered in the circulation, appear to play a central role in renal fibrosis. Pharmacologic amelioration of renal fibrosis may require methods directed at multiple factors involved in the fibrotic process, including angiotensin II, TGF-beta, and the proliferation and activation of interstitial fibroblasts.

Topics: Angiotensin II; Epithelium; Fibrosis; Humans; Kidney Failure, Chronic; Kidney Tubules; Transforming Growth Factor beta

Hepatocyte growth factor (HGF) has mitogenic, motogenic, morphogenic, and anti-apoptotic activities on renal cells and is a potential renotropin for renal protection and repair. In chronic renal failure/fibrosis, HGF in the kidney declines in a reciprocal manner to the increase in transforming growth factor-beta (TGF-beta). Neutralization of HGF by the antibody leads to acceleration of renal failure/fibrosis while HGF administration leads to remarkable attenuation, thus indicating the importance of HGF versus TGF-beta counterbalance in both pathogenesis and therapeutics in cases of chronic renal failure. HGF is being strongly considered for potential treatment of acute and chronic renal failure.

Topics: Animals; Hepatocyte Growth Factor; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Regeneration; Transforming Growth Factor beta

Chronic renal failure is the consequence of progressive glomerulosclerosis and tubulo-interstitial fibrosis. The initiating hallmark of nephrosclerosis represents nephronal hypertrophy, due to an accumulation of proteins in the glomeruli and tubulointerstitium. From experimental and clinical investigations the conclusion can be drawn that the disturbed intrarenal protein balance with the consequent nephronal hypertrophy is at least partly the result of reduced protein degradation. Potential factors involved in impaired renal proteinase activities are cytokines like transforming growth factor beta 1 (TGF-beta 1), angiotensin II and advanced glycation endproducts (AGEs).. Nephrosclerosis as the common histological endpoint of chronic renal insufficiency is the result of an interaction between many pathogenetic factors. Its growing understanding implies the possibility of new therapeutic options to retard the progressive course of chronic renal failure.

Topics: Angiotensin II; Diabetic Nephropathies; Glycation End Products, Advanced; Humans; Kidney; Kidney Failure, Chronic; Kidney Tubular Necrosis, Acute; Proteins; 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

Topics: Black People; Humans; Kidney Failure, Chronic; Models, Biological; Transforming Growth Factor beta; White People

Glomerulosclerosis and tubulointerstitial fibrosis are common morphological correlates of many end-stage kidneys. There is ample evidence that transforming growth factor-beta (TGF-beta) plays a major role in these alterations by directly stimulating synthesis of many extracellular matrix components and reducing collagenase production, finally leading to renal scarring. Although many factors may induce TGF-beta expression in the kidney, one very interesting aspect is the link between angiotensin II (ANG II) and TGF-beta. Originating from observations in vascular smooth muscle cells, there are now several additional studies showing that ANG II stimulates TGF-beta expression in the kidney. Although cell culture studies have convincingly demonstrated that the vasoactive peptide directly stimulates transcription as well as bioactivation of TGF-beta, the in vivo evidence is more indirect. Nevertheless, there are several pathophysiological situations including unilateral ureteral obstruction, chronic cyclosporin A nephrotoxicity, various models of hypertension, and probably diabetic nephropathy in which ANG II-mediated TGF-beta induction has been demonstrated to play an important role in the progression of the disease. The fascinating aspect of this relationship between ANG II and TGF-beta is the fact that hemodynamic changes as well as structural changes are linked together generating a unifying model of progression of chronic renal failure with ANG II as the key player. Angiotensin-converting enzyme (ACE) inhibitor and the more recently introduced AT1-receptor blocker may be potential drugs to interfere with this ANG II-mediated TGF-beta expression. Therefore, these drugs should not only be considered as antihypertensive medications, but should rather be viewed as renoprotective substances influencing renal remodeling by preventing local TGF-beta expression.

Topics: Angiotensin II; Animals; Gene Expression; Humans; Kidney; Kidney Failure, Chronic; Transforming Growth Factor beta

Topics: Actins; Animals; Extracellular Matrix; Glomerulosclerosis, Focal Segmental; Humans; Kidney Failure, Chronic; Models, Biological; Platelet-Derived Growth Factor; Transforming Growth Factor beta

Topics: Atrophy; Fibrosis; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Kidney Failure, Chronic; Kidney Tubules; Nephritis, Interstitial; Platelet-Derived Growth Factor; Transforming Growth Factor beta

Both angiotensin II and TGF-beta are key mediators of glomerular and tubulointerstitial injury and fibrosis in progressive kidney diseases. It was thought that angiotensin II damages the kidney by increasing glomerular filtration pressure, whereas autocrine TGF-beta overexpression occurs from unidentified mechanisms. Recent studies reveal that angiotensin II is a potent inducer of TGF-beta synthesis in a variety of cells and that this mechanism exerts important biological effects including extracellular matrix accumulation, cell proliferation, and hypertrophy. Because these studies were performed in vitro, there is clear evidence that the biological effects were observed independently of the vasoconstrictive properties of angiotensin II. Although it is difficult to study angiotensin II-mediated effects in vivo without influencing systemic and glomerular blood pressure, further studies are needed to evaluate the ability of ACE-inhibitors and angiotensin II receptor blockers to suppress TGF-beta overexpression in selected models of chronic progressive kidney disease.

Topics: Angiotensin II; Animals; Glomerular Filtration Rate; Glomerular Mesangium; Glomerulonephritis; Humans; Kidney Diseases; Kidney Failure, Chronic; Renin-Angiotensin System; Transforming Growth Factor beta

Increasing long-term allograft survival is the main challenge in organ transplantation, and allograft loss due to chronic rejection has been found to correlate with episodes of early acute rejection. It is important to understand the mechanisms that maintain the donor-specific hyporesponsive state. This study prospectively evaluates immune events related to donor-specific hyporesponsiveness in the stable transplant patients on calcineurin inhibitors (CNIs).. Peripheral blood mononuclear cells of transplant recipients on CNI (n=19) were tested in mixed lymphocyte reaction (MLR) against donor and third-party peripheral blood mononuclear cells pretransplant and at 6 to 8 weeks, 14 to 18 weeks, and 6 to 8 months posttransplant. Interleukin (IL)-10 and transforming growth factor-beta were quantitated in cultures supernatants by enzyme-linked immunosorbent assay. CD4CD25 T-regulatory cells (Tregs) were enumerated using flow cytometry.. All patients showed sharp decline in anti-donor and third-party MLR response at 6 to 8 weeks posttransplant with progressive decline up to 6 to 8 months. This was accompanied by increased IL-10 levels in the supernatant at all the follow-ups. Transforming growth factor-beta level in the supernatant was significantly lower at 14 to 18 weeks. Frequency of CD4CD25 Tregs showed a significant decrease at 6 to 8 weeks posttransplant, which was sustained up to 6 to 8 months.. The study shows that the maintenance of good graft function in early posttransplant period in recipients on CNI is associated with a decrease in donor-specific and third-party MLRs. There is a decline in Treg numbers along with increased IL-10 levels. High IL-10, probably from a non-Tregs source, may have an important role in maintaining hyporesponsiveness and good graft function.

Topics: Adult; Calcineurin Inhibitors; Cell Proliferation; Cells, Cultured; Cyclosporine; Drug Therapy, Combination; Enzyme Inhibitors; Everolimus; Female; Graft Survival; Humans; Immunosuppressive Agents; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Kidney Failure, Chronic; Kidney Transplantation; Lymphocyte Count; Lymphocyte Culture Test, Mixed; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Prospective Studies; Sirolimus; T-Lymphocytes, Regulatory; Tacrolimus; Time Factors; Transforming Growth Factor beta; Transplantation Tolerance; Up-Regulation; Young Adult

To observe the therapeutic effect of Tongluo capsule (TLC) in treating diabetic nephropathy (DN) complicated chronic renal failure (CRF), and to explore its mechanism preliminarily.. Ninety-seven patients with DN-CRF were randomly divided into the TCM group (n = 50) and the WM group (n = 47) to observe the changes of urinary protein per 24 hrs (UP/24h), renal function, creatinine (Cr), blood urea nitrogen (BUN), blood lipids (TG, TC, HDL-C, LDL-C) and serum transforming growth factor-beta1 (TGF-beta1) before and after treatment.. After 6 months of treatment, levels of UP/24h, Cr, BUN and TGF-beta1 significantly lowered in both groups (P<0.01), and a better effect was showed in the TCM group in aspects of lowering Cr, BUN and TGF-beta1 (P<0.01). Besides, TLC also showed effect in lowering the serum lipid parameters (P<0.05 or P<0.01).. Effect of TLC in treating DN-CRF might be through lowering the levels of blood lipids and serum TGF-beta1.

Topics: Adult; Albuminuria; Blood Urea Nitrogen; Capsules; Creatinine; Diabetic Nephropathies; Drugs, Chinese Herbal; Female; Humans; Kidney Failure, Chronic; Lipids; Male; Middle Aged; Phytotherapy; Tongue; Transforming Growth Factor beta; Transforming Growth Factor beta1

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

Patients with chronic renal failure (CRF) have impaired exercise capacity even after erythropoietin treatment. We recently showed that although this is explained in part by reduced convective O(2) delivery to muscles, there is also an impairment of O(2) transport from muscle capillaries to the mitochondria. Given the importance of the capillary surface area for capillary mitochondrial O(2) transport and reports of reduced capillarity in CRF, we hypothesized that the angiogenic gene response to exercise is impaired in such patients. Six patients with CRF and six control subjects matched for age, size, and sedentary lifestyle exercised on a single occasion for 1 h at similar work intensities averaging 50% of maximal capacity. Exercise was confined to the knee extensors of a single leg by means of a specially designed leg-kick ergometer. A percutaneous biopsy of the quadriceps was taken within 30 min of cessation of exercise and compared with a similar biopsy done at different times without any prior exercise for 24 h. Conventional Northern blots were prepared and probed for vascular endothelial growth factor (VEGF; the major putative angiogenic growth factor for muscle), basic fibroblast growth factor (bFGF), and transforming growth factor (TGF)-beta(1). Data during both rest and exercise were successfully obtained in four subjects of each group. We also assessed muscle capillarity and mitochondrial oxidative capacity to relate to these changes. Mitochondrial oxidative capacity was normal, whereas capillary number per fiber was 12% lower than in normal subjects. VEGF mRNA abundance was increased after exercise by about one order of magnitude, with no reduction in response in CRF. For bFGF and TGF-beta(1), exercise elicited no response in either group. Reduced muscle capillarity in CRF does not, therefore, stem from reduced transcription of VEGF. To the extent that VEGF is important to exercise-induced angiogenesis in muscle, we suspect a posttranscriptional aberration in this response occurs in CRF to explain reduced capillarity.

Topics: Adolescent; Adult; Biopsy; Blotting, Northern; Endothelial Growth Factors; Exercise; Fibroblast Growth Factor 2; Humans; Kidney Failure, Chronic; Lymphokines; Matched-Pair Analysis; Mitochondria, Muscle; Muscle, Skeletal; Oxygen Consumption; Pyruvate Dehydrogenase Complex; RNA, Messenger; Succinate Dehydrogenase; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Chronic allograft nephropathy represents the principal cause of graft loss after the first year of transplantation. Transforming growth factor-beta1 (TGF-beta1) is a key factor in fibrogenesis and has been involved in the pathogenesis of chronic allograft nephropathy and other chronic nephropathies. Experimental studies have demonstrated that the angiotensin II receptor antagonist (losartan) could decrease the synthesis of TGF-beta1. The aim of this study was to determine the plasma levels of TGF-beta1 in transplant patients with chronic allograft nephropathy, and to evaluate the effect of losartan on TGF-beta1 plasma levels and other vasoactive peptides (angiotensin II, plasma renin activity, aldosterone, endothelin-1, and nitrites and nitrates). Angiotensin-converting enzyme genotypes were also determined in all patients.. Fourteen transplant patients with chronic allograft nephropathy were included. Treatment with losartan (50 mg) was introduced. Consecutive determinations of TGF-beta1 and other vasoactive peptides were performed during follow-up.. Patients with chronic allograft nephropathy presented higher plasma levels of TGF-beta1 than the control groups. The treatment with losartan significantly decreased the plasma levels of TGF-beta1 (P < 0.05) and endothelin (P < 0.05) in all patients. The decrease of TGF-beta1 was statistically correlated with the blockade of the angiotensin II receptor (P < 0.05). No significant correlation could be demonstrated between angiotensin-converting enzyme genotypes and TGF-beta, endothelin-1, and nitrite-nitrate serum levels.. This study demonstrates that losartan significantly decreases the plasma levels of TGF-beta1, the most important fibrogenetic factor. These results could play a decisive role in the treatment and prevention of chronic nephropathies, not only graft nephropathy, because the intrinsic pathogenetic mechanism is very similar in all forms, with a crucial roles for the renal renin-angiotensin system and TGF-beta1.

Topics: Adult; Aged; Angiotensin II; Antihypertensive Agents; Blood Pressure; Chronic Disease; Endothelins; Female; Fibrosis; Follow-Up Studies; Graft Rejection; Humans; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Losartan; Male; Middle Aged; Pilot Projects; Proteinuria; Transforming Growth Factor beta; Transplantation, Homologous; Vasoconstrictor Agents

Short-term effects of recombinant human erythropoietin on serum levels of transforming growth factor beta-1, interleukin 1-alpha, interleukin 3, interferon gamma, and tumour necrosis factor alpha in patients with chronic renal failure on chronic haemodialysis were investigated. Recombinant human erythropoietin was applied subcutaneously in a dose of 75 IU/kg on 19 patients. Serum levels of transforming growth factor beta-1, interleukin 1-alpha, interleukin 3, interferon gamma, tumour necrosis factor alpha and erythropoietin, red blood cell parameters: red blood cell count, haemoglobin, haematocrit, and erythrocyte indices were determined before and after recombinant human erythropoietin single application. Transforming growth factor beta-1 serum levels were decreased after recombinant human erythropoietin (22.70 +/- 1.51 ng/ml versus 18.77 +/- 1.70 ng/ml (p < 0.01). None of the other investigated parameters was influenced significantly by recombinant human erythropoietin. Recombinant human erythropoietin in patients with chronic renal failure on chronic haemodialysis may influence anaemia not only through its stimulating effect on erythropoiesis, but also by direct oxygen-independent decrease of at least one of the negative regulators of erythropoiesis--the transforming growth factor beta.

Topics: Adult; Anemia; Erythropoietin; Female; Humans; Interferon-gamma; Interleukin-1; Interleukin-3; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

To evaluate potential adverse effects of acetate use in hemodialysis (HD), we measured plasma interleukin (IL-1 alpha, IL-1 beta, IL-6), TNF alpha, TGF beta 1, and beta 2-microglobulin levels with ELISA assays in normal (N = 9), CRF (N = 6), CAPD (N = 7) and HD (N = 8) subjects and compared the effects of acetate (Ac) and acetate-free (Ac-free) dialysate. TGF beta 1 was the only cytokine consistently detected. Compared to normals (median 57, range 53 to 68 pg/ml, one undetected; N = 8), TGF beta 1 was higher in the CRF (75, 70 to 97 pg/ml, one undetected) and CAPD (75.5, 66 to 116 pg/ml, N = 6) groups (P less than 0.05), and was somewhat higher in the HD (68, 52 to 88 pg/ml) group (P less than 0.10). Acutely, TGF beta 1 pre-HD (70, 63 to 88 pg/ml) increased above normals post AcHD [79.5, 65 to 140 pg/ml uncorrected for ultrafiltration (UF)] and was higher after AcHD versus Ac-free HD both uncorrected (79.5, 65 to 140 pg/ml vs. 70, 52 to 86 pg/ml) and corrected for UF (68, 51 to 115 pg/ml vs. 57, 43 to 69 pg/ml; P less than 0.05). beta 2-microglobulin was not different after AcHD (81.2 +/- 8.0 mg/ml) versus Ac-free HD (72.5 +/- 6.9 mg/ml). Significantly lower serum inorganic phosphorus was also found four hours post-AcHD compared to four hours post-Ac-free HD (0.87 mmol +/- 0.10 SEM vs. 1.05 mmol +/- 0.07 SEM; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetates; Acetic Acid; Adult; beta 2-Microglobulin; Female; Humans; Interleukin-1; Interleukin-6; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Leucine-rich α-2 glycoprotein 1 (LRG1) was recently identified as an amplifier of transforming growth factor-β (TGF-β)-induced kidney fibrosis in animal models. We aimed to study whether urine LRG1 is associated with risk of progression to end-stage kidney disease (ESKD) in individuals with type 2 diabetes.. A total of 1,837 participants with type 2 diabetes and estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2 were recruited from a regional hospital and a primary care facility. Association of urine LRG1 with risk of ESKD (progression to sustained eGFR <15 mL/min/1.73 m2, dialysis, or death resulting from renal causes) was assessed by survival analyses.. During a median follow-up of 8.6 (interquartile range 5.8-9.6) years, 134 incident ESKD events were identified. Compared with those in the lowest tertile, participants with baseline urine LRG1 in the highest tertile had a 1.91-fold (95% CI 1.04-3.50) increased risk of progression to ESKD, after adjustment for cardiorenal risk factors, including eGFR and albuminuria. As a continuous variable, 1 SD increment in urine LRG1 was associated with a 1.53-fold (95% CI 1.19-1.98) adjusted risk of ESKD. Of note, the association of urine LRG1 with ESKD was independent of plasma LRG1. Moreover, urine LRG1 was associated with rapid kidney function decline and progression to macroalbuminuria, two common pathways leading to ESKD.. Urine LRG1, a TGF-β signaling modulator, predicts risk of progression to ESKD independently of clinical risk factors in patients with type 2 diabetes, suggesting that it may be a novel factor involved in the pathophysiological pathway leading to kidney disease progression.

Topics: Diabetes Mellitus, Type 2; Disease Progression; Glomerular Filtration Rate; Glycoproteins; Humans; Kidney Failure, Chronic; Leucine; Transforming Growth Factor beta

Chronic kidney disease stage 5 on dialysis (CKD-5D) remains a global health problem associated with an increased risk of morbidity and mortality owing to cardiovascular disease. This condition is associated with chronic inflammation, which is characterized by an increase in cytokines, including tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β). Superoxide dismutase (SOD) is a first-line endogenous enzymatic antioxidant capable of neutralizing the effects of inflammation and oxidative stress. Therefore, the main aim of this study was to determine the effect of SOD supplementation on serum TNF-α and TGF-β levels in patients undergoing hemodialysis (CKD-5D).. A quasi-experimental study with a pretest-posttest design was conducted from October to December 2021 in the Hemodialysis Unit of Dr. Hasan Sadikin Hospital, Bandung. Patients with CKD-5D who routinely underwent hemodialysis therapy twice a week were included in the study. All participants received SOD-gliadin 250 IU twice a day for 4 weeks. Serum TNF-α and TGF-β levels were assessed before and after the intervention, and statistical analyses were performed.. This study enrolled 28 patients undergoing hemodialysis. The median age of the patients was 42 ± 11 years, with a male-to-female ratio of 1:1. The average duration of hemodialysis in the participants was 24 (5-72) months. A statistically significant decrease in serum TNF-α and TGF-β levels from 0.109 (0.087-0.223) to 0.099 (0.083-0.149) pg/mL (p=0.036) and 15.38 ± 3.64 to 13.47 ± 3.07 pg/mL (p=0.031), respectively, after SOD administration was noted.. Exogenous SOD supplementation decreased serum TNF-α and TGF-β levels in patients with CKD-5D. Further randomized controlled trials are required to confirm these findings.

Topics: Adult; Antioxidants; Dietary Supplements; Female; Hemodialysis Units, Hospital; Humans; Inflammation; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Superoxide Dismutase; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Chronic renal failure (CRF) is the result of kidney damage. Puerarin is a flavonoid with specific nephroprotective effect, but its effect on CRF needs further research. This study explored the effect of puerarin on CRF and the potential molecular mechanism.. In the CRF model, puerarin alleviated renal injury and fibrosis and reduced creatinine (Cr) and blood urea nitrogen (BUN) levels. At the same time, miR-342-3p was downregulated, while the TGF-β/SMAD axis was activated and levels of IL-1β and IL-18 were increased. After treatment of CRF rats with puerarin, the expression level of miR-342-3p was increased, the TGF-β/SMAD axis was inhibited, and the secretion of IL-1β and IL-18 was decreased. MiR-342-3p directly bound to and negatively regulated the expression of TGF-β1, SMAD2, and SMAD3. In the in vitro CRF model, miR-342-3p inhibited HK-2 cell pyroptosis by inhibiting the TGF-β/SMAD axis.. Puerarin reduced renal injury and pyroptosis in CRF rats by targeting the miR-342-3p/TGF-β/SMAD axis.

Topics: Animals; Epithelial Cells; Fibrosis; Humans; Hydrogen Peroxide; Interleukin-18; Kidney Failure, Chronic; MicroRNAs; Pyroptosis; Rats; Transforming Growth Factor beta

Renal inflammation and fibrosis are observed in underlying diseases associated with the pathological progression of chronic kidney disease (CKD). The inhibition of renal inflammation and fibrosis is one method to suppress the progression of CKD. Juzentaihoto (TJ-48), a Kampo medicine, effectively relieves chronic wasting diseases and fatigue and has been reported to decrease inflammation. In this study, we investigated whether TJ-48 has a renal protective effect and its underlying mechanism in mice with adenine-induced CKD. BALB/c mice were divided into four groups for examination: (1) control, (2) dietary restriction, (3) adenine, and (4) adenine + TJ-48. Biochemical and histological analyses, gene expression analysis, and complete blood counts were performed. TJ-48 treatment decreased tubular damage and fibrosis. TJ-48 also decreased creatinine levels exacerbated by adenine, suppressed the mRNA expression of tumor necrosis factor-α, chemokine ligand 2, transforming growth factor-β, and kidney injury molecule-1, and decreased the neutrophil/lymphocyte ratio increased by adenine. TJ-48 exerts a renoprotective effect possibly via the suppression of fibrosis and inflammation.

Topics: Adenine; Administration, Oral; Animals; Disease Models, Animal; Disease Progression; Drugs, Chinese Herbal; Fibrosis; Hepatitis A Virus Cellular Receptor 1; Inflammation; Kidney Failure, Chronic; Kidney Tubules; Mice, Inbred BALB C; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Circulating proteins associated with transforming growth factor-β (TGF-β) signaling are implicated in the development of diabetic kidney disease (DKD). It remains to be comprehensively examined which of these proteins are involved in the pathogenesis of DKD and its progression to end-stage kidney disease (ESKD) in humans. Using the SOMAscan proteomic platform, we measured concentrations of 25 TGF-β signaling family proteins in four different cohorts composed in total of 754 Caucasian or Pima Indian individuals with type 1 or type 2 diabetes. Of these 25 circulating proteins, we identified neuroblastoma suppressor of tumorigenicity 1 (NBL1, aliases DAN and DAND1), a small secreted protein known to inhibit members of the bone morphogenic protein family, to be most strongly and independently associated with progression to ESKD during 10-year follow-up in all cohorts. The extent of damage to podocytes and other glomerular structures measured morphometrically in 105 research kidney biopsies correlated strongly with circulating NBL1 concentrations. Also, in vitro exposure to NBL1 induced apoptosis in podocytes. In conclusion, circulating NBL1 may be involved in the disease process underlying progression to ESKD, and its concentration in circulation may identify subjects with diabetes at increased risk of progression to ESKD.

Topics: Cell Cycle Proteins; Diabetes Mellitus, Type 2; Disease Progression; Humans; Kidney Failure, Chronic; Neuroblastoma; Proteomics; Transforming Growth Factor beta

Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD) worldwide. Currently, there is no effective treatment to completely prevent DKD progression to ESRD. Renal fibrosis and inflammation are the major pathological features of DKD, being pursued as potential therapeutic targets for DKD.. Inflammation and renal fibrosis are involved in the pathogenesis of DKD. Anti-inflammatory drugs have been developed to combat DKD but without efficacy demonstrated. Thus, we have focused on the mechanisms of TGF-β-induced renal fibrosis in DKD, as well as discussing the important molecules influencing the TGF-β signaling pathway and their potential development into new pharmacotherapies, rather than targeting the ligand TGF-β and/or its receptors, such options include Smads, microRNAs, histone deacetylases, connective tissue growth factor, bone morphogenetic protein 7, hepatocyte growth factor, and cell division autoantigen 1.. TGF-β is a critical driver of renal fibrosis in DKD. Molecules that modulate TGF-β signaling rather than TGF-β itself are potentially superior targets to safely combat DKD. A comprehensive elucidation of the pathogenesis of DKD is important, which requires a better model system and access to clinical samples via collaboration between basic and clinical researchers.

Topics: Autoantigens; Bone Morphogenetic Protein 7; Connective Tissue Growth Factor; Diabetes Mellitus; Diabetic Nephropathies; Fibrosis; Hepatocyte Growth Factor; Histone Deacetylases; Humans; Inflammation; Kidney; Kidney Failure, Chronic; Ligands; MicroRNAs; Transforming Growth Factor beta; Transforming Growth Factors

Chronic kidney disease (CKD) is a slow-developing, progressive deterioration of renal function. The final common pathway in the pathophysiology of CKD involves glomerular sclerosis, tubular atrophy and interstitial fibrosis. Transforming growth factor-beta (TGF-β) stimulates the differentiation of fibroblasts towards myofibroblasts and the production of extracellular matrix (ECM) molecules, and thereby interstitial fibrosis. It has been shown that endoglin (ENG, CD105), primarily expressed in endothelial cells and fibroblasts, can function as a co-receptor of TGF signaling. In several human organs, endoglin tends to be upregulated when chronic damage and fibrosis is present. We hypothesize that endoglin is upregulated in renal interstitial fibrosis and plays a role in the progression of CKD. We first measured renal endoglin expression in biopsy samples obtained from patients with different types of CKD, i.e., IgA nephropathy, focal segmental glomerulosclerosis (FSGS), diabetic nephropathy (DN) and patients with chronic allograft dysfunction (CAD). We showed that endoglin is upregulated in CAD patients (p < 0.001) and patients with DN (p < 0.05), compared to control kidneys. Furthermore, the amount of interstitial endoglin expression correlated with eGFR (p < 0.001) and the amount of interstitial fibrosis (p < 0.001), independent of the diagnosis of the biopsies. Finally, we investigated in vitro the effect of endoglin overexpression in TGF-β stimulated human kidney fibroblasts. Overexpression of endoglin resulted in an enhanced ACTA2, CCN2 and SERPINE1 mRNA response (p < 0.05). It also increased the mRNA and protein upregulation of the ECM components collagen type I (COL1A1) and fibronectin (FN1) (p < 0.05). Our results suggest that endoglin is an important mediator in the final common pathway of CKD and could be used as a possible new therapeutic target to counteract the progression towards end-stage renal disease (ESRD).

Topics: Diabetic Nephropathies; Endoglin; Endothelial Cells; Fibrosis; Humans; Kidney; Kidney Failure, Chronic; Receptors, Growth Factor; Renal Insufficiency, Chronic; RNA, Messenger; Transforming Growth Factor beta

Chronic kidney disease (CKD) with underlying interstitial fibrosis is often associated with end-stage renal disease (ESRD). In the present study, we investigated the renoprotective and antifibrotic potential of nootkatone (NTK), a bioactive sesquiterpene, in an experimental model of renal fibrosis. Unilateral ureteral obstruction (UUO) model was performed to induce renal fibrosis in Balb/C mice. The animals were randomly assigned into 5 groups: sham, NTK control, UUO control, UUO and NTK 5 mg/kg, and UUO and NTK 10 mg/kg. Animals received NTK at a dose of 5 mg/kg and 10 mg/kg orally for the next 14 consecutive days. UUO induced histological alterations, accumulation of extracellular matrix (ECM) components including collagens, fibronectin, and alpha-smooth muscle actin (α-SMA), activation of the transforming growth factor-β (TGF-β)/Smad signaling and oxidative damage in the obstructed kidneys. Our study revealed that NTK (10 mg/kg) inhibits UUO mediated kidney fibrosis in vivo. Administration of NTK (10 mg/kg) prevented the activation of the TGF-β/Smad signaling, expression of ECM components, markedly attenuated the renal tubular injury and fibrosis area (% area: 6.66 ± 1.45% vs UUO: 26.33 ± 2.90%). Administration of NTK at 10 mg/kg significantly restored the endogenous antioxidants and prevented the reactive oxygen species generation (25.31 ± 1.65% vs UUO: 45.01 ± 4.85%) and reduced the level of tumor necrosis factor (TNF)-α (95.22 ± 12.39 vs UUO: 215.57 ± 60.45 pg/mg protein) in the kidneys. Altogether, our findings suggest that NTK might be a budding therapeutic candidate for renal fibrosis.

Topics: Animals; Disease Models, Animal; Fibrosis; Humans; Kidney; Kidney Failure, Chronic; Male; Mice; Polycyclic Sesquiterpenes; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Ureteral Obstruction

Topics: Genetic Predisposition to Disease; Genotype; Humans; Kidney Failure, Chronic; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Transforming Growth Factor beta; Transforming Growth Factor beta1

Intervention for end-stage kidney disease (ESKD), which is associated with adverse prognoses and major economic burdens, is challenging due to its complex pathogenesis. The study was performed to identify biomarker genes and molecular mechanisms for ESKD by bioinformatics approach.. Using the Gene Expression Omnibus dataset GSE37171, this study identified pathways and genomic biomarkers associated with ESKD via a multi-stage knowledge discovery process, including identification of modules of genes by weighted gene co-expression network analysis, discovery of important involved pathways by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, selection of differentially expressed genes by the empirical Bayes method, and screening biomarker genes by the least absolute shrinkage and selection operator (Lasso) logistic regression. The results were validated using GSE70528, an independent testing dataset.. Three clinically important gene modules associated with ESKD, were identified by weighted gene co-expression network analysis. Within these modules, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed important biological pathways involved in ESKD, including transforming growth factor-β and Wnt signalling, RNA-splicing, autophagy and chromatin and histone modification. Furthermore, Lasso logistic regression was conducted to identify five final genes, namely, CNOT8, MST4, PPP2CB, PCSK7 and RBBP4 that are differentially expressed and associated with ESKD. The accuracy of the final model in distinguishing the ESKD cases and controls was 96.8% and 91.7% in the training and validation datasets, respectively.. Network-based variable selection approaches can identify biological pathways and biomarker genes associated with ESKD. The findings may inform more in-depth follow-up research and effective therapy.

Topics: Autophagy; Biomarkers; Computational Biology; Gene Expression Profiling; Genetic Markers; Humans; Kidney Failure, Chronic; Prognosis; Protein Phosphatase 2; Protein Serine-Threonine Kinases; Retinoblastoma-Binding Protein 4; RNA Splicing; Subtilisins; Transcription Factors; Transforming Growth Factor beta; Wnt Signaling Pathway

Chronic renal failure (CRF), also known as chronic kidney disease (CKD), is a common renal disorder characterized by gradual kidney dysfunction. Molecular dissection reveals that transforming growth factor beta (TGF-β) plays a central role in the pathogenesis of CRF. However, the mechanism underlying TGF-β upregulation has not been demonstrated. Here, we verified that the elevated level of TGF-β was associated with the severity of CRF stages and the activation of TGF-β-mediated signaling in 120 renal biopsies from CRF patients. By analyzing the promoter region of the

Topics: Blotting, Western; Cell Line; Cell Nucleus; Chromatin Immunoprecipitation; Humans; Immunoprecipitation; Kidney Failure, Chronic; Mass Spectrometry; NF-kappa B; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Proteins c-fos; Renal Insufficiency, Chronic; Signal Transduction; Transcription Factor AP-1; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Animals; Cardiovascular Diseases; Humans; Inflammation; Kidney Failure, Chronic; Muscle, Skeletal; Myostatin; Renal Insufficiency, Chronic; Sarcopenia; Signal Transduction; Transforming Growth Factor beta

In end-stage renal disease (ESRD) patients receiving dialysis, anemia is common and related to a higher mortality rate. Erythropoietin (EPO) resistance and iron refractory anemia require red blood cell transfusions. Myelodysplastic syndrome (MDS) is a disease with hematopoietic dysplasia. There are limited reports regarding ESRD patients with MDS. We aim to assess whether, for ESRD patients, undergoing dialysis is a predictive factor of MDS by analyzing data from the Taiwan National Health Insurance Research Database. We enrolled 74,712 patients with chronic renal failure (ESRD) who underwent dialysis and matched 74,712 control patients. In our study, we noticed that compared with the non-ESRD controls, in ESRD patients, undergoing dialysis (subdistribution hazard ratio [sHR] = 1.60, 1.16-2.19) and age (sHR = 1.03, 1.02-1.04) had positive predictive value for MDS occurrence. Moreover, more units of red blood cell transfusion (higher than 4 units per month) was also associated with a higher incidence of MDS. The MDS cumulative incidence increased with the duration of dialysis in ESRD patients. These effects may be related to exposure to certain cytokines, including interleukin-1, tumor necrosis factor-α, and tumor growth factor-β. In conclusion, we report the novel finding that ESRD patients undergoing dialysis have an increased risk of MDS.

Topics: Adult; Aged; Anemia; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Interleukin-1; Iron; Kidney Failure, Chronic; Male; Middle Aged; Myelodysplastic Syndromes; Proportional Hazards Models; Renal Dialysis; Renal Insufficiency, Chronic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

We analyzed expression of LRG1 mRNA in glomeruli of diabetic kidneys and assessed its localization by RNA. LRG1 localized predominantly to glomerular endothelial cells, and its expression was elevated in the diabetic kidneys. LRG1 ablation markedly attenuated diabetes-induced glomerular angiogenesis, podocyte loss, and the development of diabetic glomerulopathy. These improvements were associated with reduced ALK1-Smad1/5/8 activation in glomeruli of diabetic mice. Moreover, increased plasma LRG1 was associated with worse renal outcome in patients with type 2 diabetes.. These findings identify LRG1 as a potential novel pathogenic mediator of diabetic glomerular neoangiogenesis and a risk factor in DKD progression.

Topics: Activin Receptors, Type II; Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Endothelial Cells; Female; Gene Knockdown Techniques; Glomerular Filtration Rate; Glycoproteins; Humans; Kidney Failure, Chronic; Kidney Glomerulus; Male; Middle Aged; Neovascularization, Pathologic; Podocytes; RNA, Messenger; Signal Transduction; Smad Proteins; Transforming Growth Factor beta

Chronic renal failure (CRF) is defined as a progressive and irreversible loss of renal function and associated with inflammation and oxidative stress. Salvia miltiorrhiza (SM) is an important Chinese herb used in traditional Chinese medicine for treating cardiovascular diseases. The previous studies showed the SM exhibited significant protective effects on CRF. In this present study, the metabolic profiling changes and action mechanism of SM on CRF were explored.. The aims of this study were to illustrate the metabolic profiling changes of adenine induced CRF and analyze the protective effects and action mechanisms of SM ethanol extract (SMEE) and water extract (SMWE).. The animals were divided into normal group, CRF model group, Huangkui capsule-treated group, SMEE-treated group and SMWE-treated group. The UPLC-QTOFMS coupled with multivariate statistical methods were used to explore the changes of metabolic profile in plasma, urine and renal tissue from CRF rats simultaneously after treatment with SMEE and SMWE. Hematoxylin eosin (HE) staining and Masson staining were applied to observe pathological changes in renal tissue. Biochemical indicators including serum urea nitrogen (BUN), urine protein (UP) and serum creatinine (Scr) were measured according to the manufacturer's instructions of kits. Furthermore, HK-2 cell damaged model induced by ISF was established to access the protective effects and action mechanism. The dichlorodihydrofluorescein diacetate (DCFH-DA) assay was used to determine the reactive oxygen species (ROS) and Western blot was applied to analyze the expression of pathogenesis-related proteins in different groups.. The results showed that the ethanol extract (SMEE) and water extract (SMWE) of SM significantly inhibited the elevation of serum creatinine (Scr), blood urea nitrogen (BUN), urine protein (UP) and indoxyl sulfate (ISF) in adenine-induced CRF rats, especially SMEE exhibited more significant effects. Moreover, SM extracts obviously improved the symptoms of glomerular and tubular atrophy, focal calcium deposits, interstitial fibrosis, interstitial inflammation, and renal tissues. By metabolomics analysis, fifty-nine metabolites (thirteen in plasma, twenty-seven in urine and nineteen in kidney tissue) were up-regulated or down-regulated and contributed to CRF progress. After treatment of SM extracts, the altered metabolites were restored back to normal level. These potential biomarkers underpinning the metabolic pathways are including phenylalanine metabolism, pyrimidine metabolism, purine metabolism and tryptophan metabolism. Furthermore, SM extracts prevent epithelial-mesenchymal transition (EMT) of human renal tubular epithelial (HK-2) cell by inhibiting NADPH oxidase/ROS/ERK and TGF-β/Smad signaling pathways.. SMEE and SMWE can significantly alleviate adenine-induced CRF via regulation of the metabolic profiling and modulation of NADPH oxidase/ROS/ERK and TGF-β/Smad signaling pathways, which provided important supports for the development of protective agent of SM for CRF.

Topics: Adenine; Animals; Biomarkers; Cell Line; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Humans; Kidney Failure, Chronic; Male; NADPH Oxidases; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Salvia miltiorrhiza; Smad Proteins; Transforming Growth Factor beta

We studied the diagnostic value of cytokines, including vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and interleukin-8 (IL-8), and the ratio of lactate dehydrogenase (LDH) to adenosine deaminase (ADA) in pleural fluid.. Prospective analysis of 44 inpatients or outpatients with pleural fluid, from December 2016 to March 2017 was conducted.. We enrolled patients with malignant pleural effusion (MPE, N = 15), empyema (N = 11), parapneumonic effusion (PPE, N = 7), chronic renal failure (CRF)/chronic heart failure (CHF) (N = 7), and tuberculous pleural effusion (TBPE, N = 4). The pleural fluid values of IL-8 and VEGF were significantly higher in empyema patients than in CRF/CHF or PPE patients. In all patients, the pleural fluid VEGF and IL-8 values were significantly positively correlated (r = 0.405, p = 0.006; r = 0.474, p = 0.047, respectively). TGF-β was elevated in patients with empyema, PPE, TBPE, and MPE. The pleural LDH-to-ADA ratio in patients with MPE or empyema/PPE was significantly higher than in patients with CRF/CHF or TBPE. LDH and ADA levels correlated significantly only in patients with MPE (r = 0.648, p = 0.009) and empyema/PPE (r = 0.978, p < 0.001).. VEGF and IL-8 production in the pleural cavity appear to accelerate the progression of PPE to empyema, by enhancing vascular permeability associated with inflammation. Sequential sampling would be needed to confirm this. The pleural LDH/ADA ratio may be a useful diagnostic tool for discriminating between various pleural effusion etiologies.

Topics: Adenosine Deaminase; Aged; Aged, 80 and over; Biomarkers; Diagnosis, Differential; Empyema, Pleural; Female; Heart Failure; Humans; Interleukin-8; Kidney Failure, Chronic; L-Lactate Dehydrogenase; Male; Middle Aged; Pleural Effusion; Pleural Effusion, Malignant; Pneumonia; Predictive Value of Tests; Prospective Studies; Transforming Growth Factor beta; Tuberculosis; Vascular Endothelial Growth Factor A

To explore the role of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in adenine-induced rat chronic renal failure and its underlying mechanism.. 30 Sprague Dawley (SD) rats were randomly assigned into three groups, namely sham group, adenine induction group (adenine group) and adenine induction + ω-3 PUFAs treatment group (ω-3 PUFAs group), with 10 rats in each group. Serum and kidney samples were collected after rats were sacrificed. Serum levels of Cr (creatinine) and BUN (urea nitrogen) were detected using commercial kits. HE (hematoxylin and eosin) staining was performed to evaluate the pathological changes of kidneys. Levels of oxidative stress indicators in rat kidney homogenate were detected by relative commercial kits, including SOD (superoxide dismutase), GSH (reduced glutathione), CAT (catalase), and T-AOC (total antioxidant capacity). Reactive oxygen species (ROS) production was also detected by immunofluorescence. Protein expressions of nuclear factor E2 related factor 2 (Nrf2) and transforming growth factor-beta (TGF-β)/SMAD pathway-related genes were detected by Western blot.. Serum levels of Cr and BUN in ω-3 PUFAs group were remarkably decreased compared with those of adenine group. Higher contents of SOD, GSH, CAT and T-AOC were observed in ω-3 PUFAs group compared with those of adenine group. Besides, MAD content and ROS production were lower in ω-3 PUFAs group than those of adenine group. Pathological changes of kidneys were alleviated after ω-3 PUFAs treatment. Western blot results demonstrated that ω-3 PUFAs treatment remarkably upregulates Nrf2, HO-1, NQO1, but downregulates relative genes in TGF-β/SMAD pathway.. ω-3 PUFAs alleviated adenine-induced chronic renal failure through enhancing antioxidant stress and inhibiting inflammatory response via regulating Nrf2 and TGF-β/SMAD pathway.

Topics: Adenine; Animals; Blood Urea Nitrogen; Creatinine; Fatty Acids, Omega-3; Glutathione; Kidney; Kidney Failure, Chronic; Male; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Smad Proteins; Superoxide Dismutase; Transforming Growth Factor beta

To investigate how miR-302b affect the calcium-phosphorus metabolism and vascular calcification (VC) of rats with chronic renal failure (CRF) via the regulation of bone morphogentic proteins 2/Runt-related transcription factor 3/Osterix (BMP-2/Runx2/Osterix) signaling pathway.. SD rats were selected to establish CRF rat models and assigned into Sham, CRF, CRF + miR-302b, and CRF + miR-NC groups. The biochemical indexes of rats were detected at 8th and 12th week. Besides, HE staining and Von Kossa staining were performed to monitor renal structural changes and VC respectively; and quantitative real-time PCR (qRT-PCR) and Western blotting to evaluate the expressions of miR-302b and BMP-2/Runx2/Osterix signaling pathway separately.. HE and Von Kossa staining showed evident vascular calcification in rats from CRF and CRF + miR-NC groups with a large number of black granules deposited in renal artery compared with Sham group, but was improved in rats in the CRF + miR-302b group compared to those in the CRF group. Besides, rats in the CRF group had elevated levels of Scr, BUN, P, Cys C, and PTH, as well as the mRNA and protein expression of BMP-2, Runx2, and Osterix, and reduced serum Ca and miR-302b levels in a time-dependent manner (all p <0.05), which was in a completely opposite tendency in the CRF + miR-302b group (all p <0.05).. miR-302b may improve calcium-phosphorus metabolism, and inhibit VC to alleviate the condition of CRF rats possibly associated with the BMP-2/Runx2/Osterix pathway, opening a new idea for CRF therapy.

Topics: Animals; Bone Morphogenetic Protein 2; Calcium; Cell Line, Tumor; Core Binding Factor Alpha 1 Subunit; HEK293 Cells; Humans; Kidney; Kidney Failure, Chronic; Male; MicroRNAs; Phosphorus; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Signal Transduction; Transcription Factors; Transforming Growth Factor beta; Vascular Calcification

We aimed to investigate the roles of cytokines during polyomavirus BK (BKV) reactivation in renal transplant patients. Forty-eight renal allograft recipients were enrolled, and their sera BKV viral load and mRNA expression levels of cytokines in peripheral blood mononuclear cells were measured by real-time polymerase chain reaction. Patient's age and gene expression levels of interleukin (IL)-2 (10.04 ± 2.63 vs. 8.70 ± 2.40, p = 0.049) and transforming growth factor (TGF)-β (12.58 ± 2.59 vs. 10.89 ± 1.91, p = 0.015) were significantly higher in BKV viremia (+) renal transplant patients. Multivariate logistic regression analysis revealed that age and mRNA expression levels of TGF-β, but not IL-2, significantly correlated with the presence of BKV viremia. Sera BKV viral loads showed a positive correlation with patient age and the levels of TGF-β and IL-6 mRNA. After adjusting for age and sex in the regression model, both age and TGF-β mRNA levels maintained a significant positive association with sera BKV viral loads. Serum TGF-β concentration tended to be higher in BKV viremia (+) patients (p = 0.079). In conclusion, expression levels of TGF-β were found to correlate with both BKV viremia positivity and sera BKV viral loads in renal transplant patients.

Topics: BK Virus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Leukocytes, Mononuclear; Male; Middle Aged; Polyomavirus Infections; Postoperative Complications; Prognosis; Real-Time Polymerase Chain Reaction; Risk Factors; Transforming Growth Factor beta; Tumor Virus Infections; Viral Load; Viremia

CKD is a global public health problem with significant mortality and morbidity.. We examined the multivariable association of plasma levels of IL-1, IL-1 receptor antagonist, IL-6, TNF-α, TGF-β, high-sensitivity C-reactive protein, fibrinogen, and serum albumin with progression of CKD in 3430 Chronic Renal Insufficiency Cohort study participants.. Over a median follow-up time of 6.3 years, 899 participants reached the composite end point of ≥50% decline in eGFR from baseline or onset of ESRD. Elevated plasma levels of fibrinogen, IL-6, and TNF-α and lower serum albumin were associated with a greater decline in eGFR over time. After adjusting for demographics, BP, laboratory variables, medication use, and baseline eGFR, hazard ratios for the composite outcome were greater for the patients in the highest quartile of fibrinogen (hazard ratio, 2.05; 95% confidence interval, 1.64 to 2.55; P<0.001), IL-6 (hazard ratio, 1.44; 95% confidence interval, 1.17 to 1.77; P<0.01), and TNF-α (hazard ratio, 1.94; 95% confidence interval, 1.52 to 2.47; P<0.001) compared with those in the respective lowest quartiles. The hazard ratio was 3.48 (95% confidence interval, 2.88 to 4.21; P<0.001) for patients in the lowest serum albumin quartile relative to those in the highest quartile. When also adjusted for albuminuria, the associations of fibrinogen (hazard ratio, 1.49; 95% confidence interval, 1.20 to 1.86; P<0.001), serum albumin (hazard ratio, 1.52; 95% confidence interval, 1.24 to 1.87; P<0.001), and TNF-α (hazard ratio, 1.42; 95% confidence interval, 1.11 to 1.81; P<0.001) with outcome were attenuated but remained significant.. Elevated plasma levels of fibrinogen and TNF-α and decreased serum albumin are associated with rapid loss of kidney function in patients with CKD.

Topics: Adult; Aged; C-Reactive Protein; Cytokines; Disease Progression; Female; Fibrinogen; Follow-Up Studies; Glomerular Filtration Rate; Humans; Inflammation; Interleukin-1; Interleukin-6; Kidney Failure, Chronic; Male; Middle Aged; Renal Insufficiency, Chronic; Serum Albumin; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Peritonitis, the most important limitation of peritoneal dialysis (PD), could be detected by biomarkers in dialysate effluent, representing a noninvasive method to indirectly assess the peritoneum status. The aim of our study was to test high mobility group box 1 (HMGB1) in PD patients, evaluating its role as precocious marker of peritoneum damage during peritonitis. Transforming growth factor (TGF)-β was correlated with peritoneal transport characteristics.. Six patients, treated by ambulatory PD, were enrolled. Samples were collected at the onset of peritonitis (T1) and every day until its resolution (T-end). Serum (s) and peritoneal (p) white blood cell (WBC) count was also evaluated. Peritoneal Equilibration Test evaluated the filter activity of peritoneum.. In patients with acute peritonitis, the highest serum and peritoneal HMGB1 values (64 ± 3.6 and 70 ± 5.3 ng/mL, respectively) were assessed, with a progressive decrease of their levels at the resolution time (T-end: sHMGB1:36 ± 2.5; pHMGB1:30.5 ± 7.0 ng/mL). While no differences of sWBC and pWBC were observed between baseline and T-end values, pHMGB1 levels remained higher at T-end than those observed at T0 (pHMGB1:30.5 ± 7.0 versus 6.9 ± 3.6; p < 0.0001). TGF-β levels were higher in patients with low peritoneal permeability than in medium or high transporter patients (81 ± 15.5 versus 24.3 ± 7.5 pg/mL; p = 0.01). An inverse correlation was found between TGF-β levels and dialysate/plasmatic creatinine values (r = -0.83; p = 0.03).. HMGB1 represents a useful biomarker for peritoneum evaluation in PD patients. A prognostic role of this alarmin, as a marker of response to therapy, could be hypothesized. TGF-β could predict the peritoneal transport status and dialysis technique adequacy.

Topics: Adolescent; Biomarkers; Child; Child, Preschool; Disease Progression; Female; HMGB1 Protein; Humans; Kidney Failure, Chronic; Male; Peritoneal Dialysis; Peritonitis; Prognosis; Transforming Growth Factor beta

Chronic kidney disease (CKD) results from the development of fibrosis, ultimately leading to end-stage renal disease (ESRD). Although human bone marrow-derived mesenchymal stem cells (MSCs) can accelerate renal repair following acute injury, the establishment of fibrosis during CKD may affect their potential to influence regeneration capacity. Here we tested the novel combination of MSCs with the antifibrotic serelaxin to repair and protect the kidney 7 d post-unilateral ureteral obstruction (UUO), when fibrosis is established. Male C57BL6 mice were sham-operated or UUO-inured (n = 4-6) and received vehicle, MSCs (1 × 10(6)), serelaxin (0.5 mg/kg per d), or the combination of both. In vivo tracing studies with luciferin/enhanced green fluorescent protein (eGFP)-tagged MSCs showed specific localization in the obstructed kidney where they remained for 36 h. Combination therapy conferred significant protection from UUO-induced fibrosis, as indicated by hydroxyproline analysis (P < 0.001 vs. vehicle, P < 0.05 vs. MSC or serelaxin alone). This was accompanied by preserved structural architecture, decreased tubular epithelial injury (P < 0.01 vs. MSCs alone), macrophage infiltration, and myofibroblast localization in the kidney (both P < 0.01 vs. vehicle). Combination therapy also stimulated matrix metalloproteinase (MMP)-2 activity over either treatment alone (P < 0.05 vs. either treatment alone). These results suggest that the presence of an antifibrotic in conjunction with MSCs ameliorates established kidney fibrosis and augments tissue repair to a greater extent than either treatment alone.

Topics: Animals; Cell Differentiation; Cell Proliferation; Collagen; Fibrosis; Gelatinases; Green Fluorescent Proteins; Humans; Kidney; Kidney Failure, Chronic; Macrophages; Male; Matrix Metalloproteinase 2; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Myofibroblasts; Recombinant Proteins; Regeneration; Relaxin; Renal Insufficiency, Chronic; Transforming Growth Factor beta

Zinc-α2-glycoprotein (AZGP1) is a secreted protein synthesized by epithelial cells and adipocytes that has roles in lipid metabolism, cell cycling, and cancer progression. Our previous findings in AKI indicated a new role for AZGP1 in the regulation of fibrosis, which is a unifying feature of CKD. Using two models of chronic kidney injury, we now show that mice with genetic AZGP1 deletion develop significantly more kidney fibrosis. This destructive phenotype was rescued by injection of recombinant AZGP1. Exposure of AZGP1-deficient mice to cardiac stress by thoracic aortic constriction revealed that antifibrotic effects were not restricted to the kidney but were cardioprotective. In vitro, recombinant AZGP1 inhibited kidney epithelial dedifferentiation and antagonized fibroblast activation by negatively regulating TGF-β signaling. Patient sera with high levels of AZGP1 similarly attenuated TGF-β signaling in fibroblasts. Taken together, these findings indicate a novel role for AZGP1 as a negative regulator of fibrosis progression, suggesting that recombinant AZGP1 may have translational effect for treating fibrotic disease.

Topics: Adipokines; Animals; Aorta; Carrier Proteins; Cell Differentiation; Epithelium; Fibroblasts; Fibrosis; Gene Deletion; Glycoproteins; HEK293 Cells; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Male; Mice; Myocardium; Phosphorylation; Protein Biosynthesis; Rats; Recombinant Proteins; Seminal Plasma Proteins; Signal Transduction; Transforming Growth Factor beta; Ureteral Obstruction; Zn-Alpha-2-Glycoprotein

We evaluated the relationship of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) levels with graft function in kidney transplantation patients receiving tacrolimus-based immunosuppression during the early post-transplantation period.. There were 112 patients who underwent kidney transplantation from live donors between May 2011 and May 2013. Eight patients had at least 1 of the exclusion criteria, and the remaining 104 patients were included in the study. The recipients underwent evaluation for biochemical markers, complete blood count, and creatinine and cytokine (IL-10, TGF-β) levels during the pretransplantation and post-transplantation 6 months.. The creatinine level was negatively correlated with IL-10 and positively correlated with TGF-β levels in both the pretransplantation and early post-transplantation period.. Low serum TGF-β and high IL-10 levels at post-transplantation month 6 might have a positive effect on graft survival in living donor kidney recipients on tacrolimus-based immunosuppressive treatment.

Topics: Adult; Biomarkers; Creatinine; Cytokines; Female; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Interleukin-10; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Tacrolimus; Transforming Growth Factor beta

The race-specific association of inflammation with adiposity and muscle mass in subjects with chronic kidney disease (CKD) was examined.. Plasma concentration of interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), IL-6, IL-10, tumor necrosis factor (TNF)-α, TGF-β, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and serum albumin was measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Bioelectric impedance analysis was used to determine body fat mass (BFM) and fat-free mass (FFM).. Plasma levels of hs-CRP, fibrinogen, IL-1RA, IL-6, and TNF-α increased and serum albumin decreased across the quartiles of body mass index. In multivariable analysis, BFM and FFM were positively associated with hs-CRP, fibrinogen, IL-1β, IL-1RA, and IL-6. One standard deviation (SD) increase in BFM and FFM was associated with 0.36 (95% confidence interval [CI] = 0.33, 0.39) and 0.26 (95% CI = 0.22, 0.30) SD increase in log-transformed hs-CRP, respectively (P < 0.001). Race stratified analysis showed that the association between biomarkers and BFM and FFM differed by race, with Caucasians, demonstrating a stronger association with markers of inflammation than African Americans.. BFA and FFM are positively associated with markers of inflammation in patients with CKD. Race stratified analysis showed that Caucasians have a stronger association with markers of inflammation compared to African Americans.

Topics: Adiposity; Adult; Aged; Biomarkers; Black or African American; Body Mass Index; C-Reactive Protein; Cohort Studies; Cross-Sectional Studies; Electric Impedance; Fibrinogen; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-1beta; Interleukin-6; Kidney Failure, Chronic; Linear Models; Middle Aged; Multivariate Analysis; Serum Albumin; Socioeconomic Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; White People

There is increasing evidence that long-term peritoneal dialysis (PD) is associated with structural changes in the peritoneal membrane. Inhibition of the renin-angiotensin system has been demonstrated to lessen peritoneal injury and to slow the decline in residual renal function. Whether spironolactone affects residual renal function in addition to the peritoneal membrane is unknown. We evaluated 23 patients (13 women) with a glomerular filtration rate of 2 mL/min/1.73 m2 or more who were receiving PD. Patients with an active infection or peritonitis episode were excluded. Baseline measurements were obtained for serum high-sensitivity C-reactive protein (hs-CRP), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-beta), and connective tissue growth factor (CTGF); for daily ultrafiltration (in milliliters); for end-to-initial dialysate concentration of glucose (4/D0 glucose), Kt/V, and peritoneal transport status; and for dialysate cancer antigen 125 (CA125). Spironolactone therapy (25 mg) was given daily for 6 months, after which all measurements were repeated. Mean age of the patients was 46 +/- 13 years. Duration of PD was 15 +/- 21 months (range: 2-88 months). After spironolactone therapy, mean dialysate CA125 was significantly increased compared with baseline (20.52 +/- 12.06 U/mL vs. 24.44 +/- 13.97 U/mL, p = 0.028). Serum hs-CRP, VEGF, TGF-beta, CTGF, daily ultrafiltration, D/Do glucose, Kt/V and peritoneal transport status were similar at both times. At the end of the study period, residual glomerular filtration rate in the patients was lower. In PD patients, treatment with spironolactone seems to slow the decline of peritoneal function, suppress the elevation of profibrotic markers, and increase mesothelial cell mass.

Topics: Adult; Aged; Biomarkers; CA-125 Antigen; Connective Tissue Growth Factor; Diuretics; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Peritoneum; Spironolactone; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Young Adult

The aim of the present study was to assess the influence of peritoneal permeability expressed as the dialysate-to-plasma ratio of creatinine (D/P Cr) on total and cardiovascular (CV) mortality in a population of peritoneal dialysis (PD) patients during a 6-year observation period. The study recruited 55 patients (mean age: 53 years) treated with PD for a median of 24 months. Hematology parameters and serum albumin were determined using routine methods. Tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta1) were determined by high-sensitivity ELISA. Peritoneal transport characteristics were identified using D/P Cr reference values after a peritoneal equilibration test. During the 6-year observation period, 22 patients (40%) died, mostly from CV complications (77% of deaths). In multiple Cox regression, D/P Cr and dialysate volume at PD initiation predicted total [hazard ratio (HR): 1.57; p = 0.02; and HR: 1.20; p = 0.04 respectively] and CV mortality (HR: 1.65; p = 0.02; and HR: 1.23; p = 0.05 respectively) independent of age, dialysis therapy duration, serum albumin concentration, dialysis adequacy measures, TGF-beta1, and TNF-alpha. Additionally, TNF-alpha was independently associated with all-cause and CV mortality, and albumin, with all-cause mortality. Baseline D/P Cr was a strong independent marker of survival in PD patients. Baseline D/P Cr and dialysate volume were independent risk factors for total and CV mortality in the PD population and could be significant for assessing CV risk in this population.

Topics: Adult; Aged; Biological Transport; Cardiovascular Diseases; Creatinine; Dialysis Solutions; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Peritoneum; Permeability; Risk Factors; Survival Rate; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Continuous ambulatory peritoneal dialysis (CAPD) induces structural changes in the peritoneal membrane such as fibrosis, vasculopathy and angioneogenesis with a reduction in ultrafiltration capacity. Leukotriene (LT) receptor antagonists have been found to be effective to prevent fibrosis in some nonperitoneal tissues. The aim of this study is to investigate the possible beneficial effect of montelukast, a LT receptor antagonist, on peritoneal membrane exposed to hypertonic peritoneal dialysis in uremic rats.. Of the 48 male, 5/6 nephrectomized Wistar rats 29 remained alive and were included in the study. These studied rats were divided into 3 groups: Group I (n=7) was the control group, Group II (n=8) was treated with 20 ml hypertonic PDF intraperitoneally daily and Group III was treated with montelukast and similar PDF treatment protocol. The morphological and functional changes in the peritoneal membrane as well as cytokine expression were compared between groups.. Submesothelial thickness and the severity of the degree of hyaline vasculapathy were more prominent in group III when compared to group I. There were no significant differences between group II and other groups in terms of submesothelial thickness and the severity of the degree of hyaline vasculapathy. Increased expressions of TGF-β and VEGF in parietal peritoneal membrane were found in group II and group III when compared to group I. The amount of TGF-β and VEGF expression were similar in group II and group III.. This study suggests that montelukast treatment does not prevent the peritoneal membrane from deleterious effects of hyperosmolar PDF in the uremic environment.

Topics: Acetates; Animals; Cyclopropanes; Cytokines; Fibrosis; Kidney Failure, Chronic; Leukotriene Antagonists; Male; Membranes; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Quinolines; Rats; Rats, Wistar; Sulfides; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

The purpose of this study was to investigate possible healing effects of intraperitoneal (IP) mesenchymal stem cell (MSC) transplantation on ultrafiltration failure (UFF) in a chronic rat model of peritoneal dialysis (PD).. Rats were initially divided into two groups. The APUF group received once-daily IP injections of 20 mL of 3.86% glucose PD solution for 6 weeks to stimulate the development of UFF and a control group received noinjections. The PUF group was sub-divided into three groups: a PUF-C group, an MSC group and a Placebo (P) group. Peritoneal equilibration tests (PETs) and peritoneal biopsies were performed in the control and PUF-C groups. MSCs were administered by IP injection in the MSC group and the PUF-C and P groups received IP injection of placebo. PETs and peritoneal biopsies were performed in the MSC and P groups at the first [P-1 (and MSC-1 groups] and second [P-2 and MSC-2 groups] week after receiving MSCs or placebo.. When compared with the control group, ultrafiltration capacity significantly decreased and the submesothelial thickness increased in the PUF-C and P groups (P-1, P-2) (P < 0.05), but there were no differences between the control and MSC groups (MSC-1, MSC-2). The rate of glucose transport was high in the PUF-C and P-2 groups compared with the control group, and D/PCr rates in the PUF-C and P-2 groups were lower than in the control group (P < 0.05). However, D/D0(glucose) was higher and D/P(Cr)was lower in the MSC-2 group than in the PUF-C and P-2 groups (P < 0.05). Transforming growth factor-β (TGF-β) levels were lower in the MSC groups than in the P and PUF-C groups (P < 0.05).. The PUF-C group had a high permeability UFF. These results showed that MSC transplantation exerted positive effects on UFF in a chronic rat model of PD. MSC transplantation may provide new options for the renewal of the peritoneum in chronic PD patients with UFF.

Topics: Animals; Biological Transport; Cell Membrane Permeability; Chronic Disease; Dialysis Solutions; Kidney Failure, Chronic; Male; Mesenchymal Stem Cell Transplantation; Peritoneal Dialysis; Peritoneum; Rats; Rats, Wistar; Transforming Growth Factor beta; Treatment Failure; Ultrafiltration

The kidney transplant is the main therapeutic alternative for end-stage kidney disease, and rejection is a major complication. The expression of proinflammatory cytokines is related to graft loss, whereas anti-inflammatory cytokines are associated with graft protection. The objective of this study is to evaluate the "in situ" expression of cytokines T helper 1 (tumor necrosis factor α [TNF-α]), T helper 17 (interleukin 17 [IL-17]), and regulatory T cell (transforming growth factor β [TGF-β]) and the expression of forkhead box P3 (FoxP3) in allograft kidney. We evaluated in situ expression of cytokines in allograft kidney under rejection process by indirect immunohistochemistry. Eighteen renal graft biopsies were from patients with episodes of rejection. The in situ expression of IL-17, TNF-α, and TGF-β was significantly higher in patients with acute rejection when compared with the control group. In contrast, analysis of FoxP3 expression showed few positive cells in patients with acute rejection compared with the control group. The results suggest that the expression of proinflammatory cytokines (IL-17 and TNF-α) contributes to the mechanisms of kidney transplant rejection. The increase in TGF-β expression might be an attempt to establish a process of immunoregulation or even to induce higher production of IL-17. The last hypothesis is supported by the observation of a reduced expression of FoxP3 and elevated levels of IL-17.

Topics: Adult; Aged; Biomarkers; Biopsy; Case-Control Studies; Down-Regulation; Female; Forkhead Transcription Factors; Graft Rejection; Humans; Interleukin-17; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Transcriptome; Transforming Growth Factor beta; Transplantation, Homologous; Tumor Necrosis Factor-alpha; Up-Regulation

Dietary sodium chloride (salt) has long been considered injurious to the kidney by promoting the development of glomerular and tubulointerstitial fibrosis. Endothelial cells throughout the vasculature and glomeruli respond to increased dietary salt intake with increased production of transforming growth factor-β (TGF-β) and nitric oxide. High-salt intake activates large-conductance, voltage- and calcium-activated potassium (BK(Ca)) channels in endothelial cells. Activation of BK(Ca) channels promotes signaling through proline-rich tyrosine kinase-2, cellular-sarcoma (c-Src), Akt (also known as protein kinase B), and mitogen-activated protein kinase pathways that lead to endothelial production of TGF-β and nitric oxide. TGF-β signaling is broadly accepted as a strong stimulator of renal fibrosis. The classic description of TGF-β signaling pathology in renal disease involves signaling through Smad proteins resulting in extracellular matrix deposition and fibrosis. Active TGF-β1 also causes fibrosis by inducing epithelial-mesenchymal transition and apoptosis. By enhancing TGF-β signaling, increased dietary salt intake leads to progressive renal failure from nephron loss and glomerular and tubulointerstitial fibrosis.

Topics: Animals; Endothelial Cells; Epithelial-Mesenchymal Transition; Fibrosis; Focal Adhesion Kinase 2; Humans; Kidney; Kidney Failure, Chronic; Large-Conductance Calcium-Activated Potassium Channels; Mice; Mitogen-Activated Protein Kinases; Nitric Oxide; Proto-Oncogene Proteins c-akt; Rats; Renal Insufficiency, Chronic; Signal Transduction; Smad Proteins; Sodium Chloride, Dietary; src-Family Kinases; Transforming Growth Factor beta; Transforming Growth Factor beta1

Obstructive nephropathy is a leading cause of CKD in children. The assessment of severity of renal impairment and the prediction of which children will progress to renal failure are, however, challenging.. This case-control study measured the urinary excretion of candidate biomarkers in 27 prevalent case-patients with posterior urethral valves (PUVs) and 20 age-matched controls, correlated their urinary concentration with GFR, and analyzed receiver-operating characteristic (ROC) curve and regression analyses to assess their performance as tests for low GFR.. The median urinary protein-to-creatinine ratio was higher in children with PUV (45 g/mol; range, 5-361 g/mol) than in controls (7 g/mol; range, 3-43 g/mol) (P<0.01) and correlated inversely with renal function (r = -0.44; P<0.05). In whole urine, excretion of aquaporin-2 was significantly decreased, whereas that of TGFβ and L1 cell adhesion molecule (L1CAM) was significantly increased. Whole-urine TGFβ excretion correlated inversely with GFR (r = -0.53; P<0.05). As tests for low GFR, whole-urine TGFβ, L1CAM, and urinary protein-to-creatinine ratio performed best, with areas under the ROC curves of 0.788, 0.795, and 0.814, respectively. By linear regression analysis, whole-urine TGFβ, L1CAM, and urinary protein-to-creatinine ratio were associated with low GFR in the case-patients.. Candidate biomarkers of obstructive nephropathy can be readily measured in whole urine and in urine exosomes. In boys with PUV, these biomarkers correlate with GFR.

Topics: Adolescent; Antigens, CD; Aquaporin 2; Area Under Curve; beta Catenin; Biomarkers; Cadherins; Case-Control Studies; Child; Child, Preschool; Creatinine; Disease Progression; Exosomes; Feasibility Studies; Glomerular Filtration Rate; Humans; Infant; Kidney; Kidney Diseases; Kidney Failure, Chronic; Linear Models; Logistic Models; Male; Neural Cell Adhesion Molecule L1; Predictive Value of Tests; Proteinuria; Proteomics; ROC Curve; Transforming Growth Factor beta; TRPV Cation Channels; Urethral Obstruction; Urinalysis; Vacuolar Proton-Translocating ATPases

Renal fibrosis is the final common pathway of chronic kidney disease, and its progression predicts the degree of renal dysfunction. We investigated the renoprotective properties of pirfenidone in a remnant kidney model of chronic renal failure to determine its pharmacological potency compared to enalapril. Five-sixths nephrectomized rats were fed diet containing pirfenidone (approximately 700mg/kg/day) for 8weeks. Pirfenidone steadily inhibited the progression of proteinuria, but not to a significant degree. Pirfenidone prevented the elevation of plasma creatinine and blood urea nitrogen. At the end of the experiment, pirfenidone had reduced systolic blood pressure by means of its renoprotective effect. In a histological study, pirfenidone improved interstitial fibrosis in the renal cortex. These effects were supported by the suppression of the expression of TGF-beta and fibronectin in the mRNA of the kidney. In contrast, pirfenidone had little effect on the expression of alpha-smooth muscle actin, which is one of the proteins responsible for epithelial-mesenchymal transition. This property was confirmed by the TGF-beta-induced transdifferentiation observed in cultured normal rat kidney tubular epithelial NRK52E cells. These results suggest that pirfenidone improves the progression of chronic renal failure via its antifibrotic action, although pirfenidone has less effective TGF-beta-induced epithelial to mesenchymal transdifferentiation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Differentiation; Cell Line; Chronic Disease; Disease Progression; Enalapril; Epithelial Cells; Fibrosis; Kidney; Kidney Failure, Chronic; Male; Mesoderm; Nephrectomy; Proteinuria; Pyridones; Rats; Rats, Wistar; Transforming Growth Factor beta

The association between peritoneal solute transport rates (PSTRs) and inflammatory markers in patients on peritoneal dialysis (PD) is still under investigation. We aimed to elucidate their relationship during the first year on PD.. We performed a prospective observational study with 187 incident PD patients who were treated with either biocompatible solution (BCS) or conventional solution (CS). Peritoneal dialysate effluent (PDE) and blood samples for the markers and the calculation of mass transfer area coefficient of creatinine (MTAC) were performed at 1, 6 and 12 months after commencing PD.. Of the 187 enrolled patients, 110 completed a 1-year study protocol. All PDE markers [interleukin-6 (IL-6), transforming growth factor-beta (TGF-beta), TGF-beta-induced gene-h3 (beta ig-h3), vascular endothelial growth factor (VEGF)] except CA125 increased over time, whereas PSTRs, high-sensitivity C-reactive protein (hs-CRP) and serum IL-6 levels did not change. Serum albumin and log PDE appearance rates (ARs) of IL-6, TGF-beta and CA125 predicted MTAC. The Delta value (12-month minus 1-month) of PDE AR of IL-6 was correlated with those of all other PDE markers. Both 12-month IL-6 and Delta IL-6 ARs in PDE were highest in the upper Delta MTAC tertile. PSTRs in the CS group, unlike BCS, had a tendency to increase over time, demonstrating a time-by-group interaction. Solution type and MTAC were not associated with patient and technique survival.. The change in PSTR during the first year of PD is related to PDE IL-6 AR, which may represent intraperitoneal inflammation; however, there does not seem to be a close association between PSTR and the degree of systemic inflammation.

Topics: Adult; Aged; Biological Transport, Active; Biomarkers; CA-125 Antigen; Creatinine; Cytokines; Dialysis Solutions; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Membrane Proteins; Middle Aged; Peritoneal Dialysis; Peritoneum; Peritonitis; Permeability; Prospective Studies; Transforming Growth Factor beta

Most forms of chronic kidney disease are characterized by progressive renal and cardiac fibrosis leading to dysfunction. Preliminary evidence suggests that various bone marrow-derived cell populations have antifibrotic effects. In exploring the therapeutic potential of bone marrow derived cells in chronic cardio-renal disease, we examined the anti-fibrotic effects of bone marrow-derived culture modified cells (CMCs) and stromal cells (SCs).. In vitro, CMC-conditioned medium, but not SC-conditioned medium, inhibited fibroblast collagen production and cell signalling in response to transforming growth factor-beta. The antifibrotic effects of CMCs and SCs were then evaluated in the 5/6 nephrectomy model of chronic cardio-renal disease. While intravascular infusion of 10(6) SCs had no effect, 10(6) CMCs reduced renal fibrosis compared to saline in the glomeruli (glomerulosclerosis index: 0.8+/-0.1 v 1.9+/-0.2 arbitrary units) and the tubulointersitium (% area type IV collagen: 1.2+/-0.3 v 8.4+/-2.0, p<0.05 for both). Similarly, 10(6) CMCs reduced cardiac fibrosis compared to saline (% area stained with picrosirius red: 3.2+/-0.3 v 5.1+/-0.4, p<0.05), whereas 10(6) SCs had no effect. Structural changes induced by CMC therapy were accompanied by improved function, as reflected by reductions in plasma creatinine (58+/-3 v 81+/-11 micromol/L), urinary protein excretion (9x/divided by 1 v 64x/divided by 1 mg/day), and diastolic cardiac stiffness (left ventricular end-diastolic pressure-volume relationship: 0.030+/-0.003 v 0.058+/-0.011 mm Hg/microL, p<0.05 for all). Despite substantial improvements in structure and function, only rare CMCs were present in the kidney and heart, whereas abundant CMCs were detected in the liver and spleen.. Together, these findings provide the first evidence suggesting that CMCs, but not SCs, exert a protective action in cardio-renal disease and that these effects may be mediated by the secretion of diffusible anti-fibrotic factor(s).

Topics: Animals; Bone Marrow Cells; Collagen; Creatinine; Culture Media, Conditioned; Disease Models, Animal; Disease Progression; Fibrosis; Glomerulonephritis; Heart Injuries; Kidney; Kidney Failure, Chronic; Male; Rats; Rats, Inbred F344; Stromal Cells; Transforming Growth Factor beta

Erythropoiesis-stimulating agents (ESAs) may have therapeutic benefits beyond ameliorating anemia. Although ESAs have renoprotective effects in acute/chronic renal injury models, their effects on blood pressure could also worsen chronic renal failure (CRF). The development of human cell-derived erythropoietin analogue epoetin delta prompted us (1) to investigate whether in a 5/6th nephrectomy-induced CRF rat model, epoetin delta-mediated renoprotective effects occur independently of its hematopoietic effects and (2) to unravel the involvement of particular factors herein.. After induction of CRF in Wistar rats, epoetin delta was administered for 8 weeks at different doses: 0 IU/kg (uremic control); 48, 100 or 300 IU/kg 1x/week, and 16 or 100 IU/kg 3x/week. During this period hematopoietic and renal functional parameters as well as systolic blood pressure (SBP) were monitored.. After 8 weeks, control CRF rats showed reduced hematocrit (Hct)/hemoglobin (Hb) levels and increased SBP. Epoetin delta dose-dependently attenuated the reduction in Hct/Hb. Furthermore, epoetin delta treatment resulted in reduced deterioration of renal function in CRF rats after 8 weeks which was accompanied by decreased collagen deposition, renal fibrosis and interstitial macrophage infiltration. Remarkably, these renoprotective effects did not show the same dose dependency as compared to that seen for the hematopoietic response and were also seen at subhematopoietic doses. Interestingly, epoetin delta treatment resulted in a dose-dependent decrease of profibrotic (TGF-beta) and proapoptotic (Bcl-2-associated X protein) genes together with a significant dose-dependent increase of antifibrotic (hepatocyte growth factor) and antiapoptotic (Bcl-2) genes. Epoetin delta treatment had no effect on VEGF expression.. Epoetin delta treatment could delay the progression of CRF through antiapoptotic and antifibrotic mechanisms. This protective action of epoetin delta on the kidney probably is not directly related to its hematopoietic effects.

Topics: Anemia; Animals; Apoptosis; bcl-2-Associated X Protein; Blood Pressure; Disease Models, Animal; Disease Progression; Erythropoietin; Fibrosis; Hematinics; Hepatocyte Growth Factor; Humans; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Rats; Rats, Wistar; Recombinant Proteins; Transforming Growth Factor beta

The most commonly used therapeutic targets in nephrology are the reduction of injury, the delay of progression, or renal replacement therapy. Many animal and human studies demonstrated the role of stem cells in repair and regenerations of kidney. Mesenchymal stem cells (MSCs) have shown to improve outcome of acute renal injury models. It is controversial whether MSCs can reduce injury following a toxic/ischemic event and delay renal failure in chronic kidney disease. We evaluated the hypothesis that the treatment with MSCs could improve renal function and attenuate injury in chronic renal failure (CRF). Sprague-Dawley female rats (8 weeks old, 182.2 +/- 7.2 g) underwent modified 5/6 nephrectomy. Rats in the MSC group received an injection of MSCs (1 x 10(6) cells) via tail vein 1 day after nephrectomy. Blood and urine samples were collected after 7 days and every month thereafter. The kidneys of rats were removed for histologic evaluation after 24-h urine collection and blood sampling. The Y-chromosome stain using fluorescent in situ hybridization was performed to verify the presence of male MSCs in the kidney of female recipients. No significant differences in blood urea nitrogen and creatinine concentration were observed between the MSC group and the untreated CRF group. However, the weight gain in the MSC group was greater than those in the CRF group after 4 months. Proteinuria in the MSC group was less than that in the CRF group over time. Y chromosome was detected in the kidney of MSC group. Although no significances were observed between these two groups, the histologic analysis suggests that MSCs have positive effect against glomerulosclerosis. These results suggest that MSCs help preserve renal function and attenuate renal injury in CRF.

Topics: Animals; Blood Urea Nitrogen; Cell- and Tissue-Based Therapy; Creatinine; Disease Progression; Female; Humans; In Situ Hybridization, Fluorescence; Kidney; Kidney Failure, Chronic; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Nephrectomy; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

We measured the neutrophil gelatinase-associated lipocalin (NGAL) concentration in peritoneal dialysate effluent (PDE) collected following an acute episode of continuous ambulatory peritoneal dialysis (CAPD)-related peritonitis.. NGAL concentration in PDE increased in the first 3 days after developing peritonitis and correlated well with the neutrophil count. In patients with culture-negative peritonitis, the NGAL in PDE was lower than that in patients with gram-positive or gram-negative peritonitis. Apart from providing additional diagnostic support to bacterial-induced peritonitis, measurement of NGAL in PDE may be useful to differentiate the neutrophil-dependent culture-negative peritonitis from that associated with non-bacterial or non-cellular etiologies.. Human peritoneal mesothelial cell (HPMC) is another source of NGAL during peritonitis. NGAL was specifically induced in HPMC by IL-1beta. Incubation of HPMC with recombinant NGAL reversed the transforming growth factor-beta-induced up-regulation of Snail and vimentin but rescued the down-regulation of E-cadherin. Our data suggest that NGAL may exert a protective effect in modulating the epithelial-to-mesenchymal transition activated following peritonitis.

Topics: Acute-Phase Proteins; Adult; Ambulatory Care; Biomarkers; Cadherins; Cell Movement; Cells, Cultured; Early Diagnosis; Gene Expression Regulation; Humans; Interleukin-1beta; Kidney Failure, Chronic; Lipocalin-2; Lipocalins; Male; Middle Aged; Neutrophils; Peritoneal Dialysis; Peritonitis; Proto-Oncogene Proteins; Snail Family Transcription Factors; Streptococcal Infections; Streptococcus; Transcription Factors; Transforming Growth Factor beta; Vimentin

Naturally occurring regulatory T cells have been associated with long-term allograft survival. We investigated whether gene transcripts of Treg-related molecules are upregulated or downregulated in kidney transplant recipients with different clinical outcomes and may serve as markers of operative tolerance.. Expression levels of transcription factor (forkhead box P3 [FOXP3], t-bet, and GATA3), regulatory molecule (cytotoxic T-lymphocyte antigen-4, glucocorticoid-induced tumor necrosis factor receptor-related protein, tribbles protein-1, and transforming growth factor-beta), and chemokine receptor (CCR7 and CXCR4) genes were measured in kidney graft recipients with long-term (> or = 9 years) stable renal function (LTS) or chronic rejection (ChrRx). Patients on dialysis and healthy individuals served as controls.. The level of FOXP3 transcripts was lower in ChrRx patients than in LTS patients (P<0.01). The highest transforming growth factor-beta transcripts were observed in ChrRx and the highest CCR7 and CXCR4 transcripts were observed in LTS patients. In LTS patients, FOXP3 gene expression was associated with CXCR4 gene expression (P=0.015). FOXP3 and CCR7 transcript levels were higher in LTS patients without calcineurin inhibitor therapy than in LTS patients with calcineurin inhibitors.. Our results suggest that high expression of FOXP3 and chemokine receptor genes in LTS patients are possible indicators of a regulatory process that contributes to long-term allograft acceptance. Markers that were increased in LTS patients were found to be decreased in ChrRx patients, suggesting that rejection may partly be the result of a lack of this regulatory process. FOXP3 and CCR7 and CXCR4 transcripts might be used as markers to distinguish patients who developed long-term allograft acceptance from patients who are prone to ChrRx.

Topics: Adult; Aged; Female; Forkhead Transcription Factors; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Postoperative Period; Receptors, CXCR; Receptors, CXCR4; Reference Values; Renal Dialysis; T-Lymphocytes, Regulatory; Transcription, Genetic; Transforming Growth Factor beta; Transplantation, Homologous; Treatment Outcome

The renin-angiotensin system (RAS) plays a critical role in chronic renal failure associated with heart failure. In the past few years, angiotensin (Ang) (1-7) have been reported to counteract the effects of angiotensin II (Ang II) and were even considered as a new therapeutical target in RAS. The purposes of this study were to examine whether the Ang (1-7) improves the heart function and remodeling of the left ventricle (LV) in mice with 5/6 nephrectomy (NC). We used a 5/6 nephrectomy to induce significant renal dysfunction in wildtype mice (WT). Twelve weeks after NC, WT showed high blood pressure, significant left-ventricular dilation and dysfunction, which were accompanied by cardiomyocyte hypertrophy, diffuse interstitial fibrosis and oxidative damage of cardiomyocytes. Exogenous Ang (1-7) injection improved the heart function and remodeling of LV in mice with 5/6 NC accompanied by a reduction in cardiac interstitial fibrosis, inflammatory cytokine expression and oxidative damage levels of cardiomyocytes, decrease in the profibrotic signaling molecule transforming growth factor (TGF)-beta and increase in the collagen degradation signaling molecule matrix metalloproteinase (MMP)-2, -9. However, these beneficial effects did not occur in hydralazine-treated mice. These findings suggest that (1) Exogenous Ang (1-7) injection improve the heart function and remodeling of LV in mice with 5/6 NC. (2) These beneficial effects are independent of its anti-blood pressure effect.

Topics: Angiotensin I; Animals; Antihypertensive Agents; Blood Pressure; Creatinine; Heart Failure; Heart Ventricles; Kidney; Kidney Failure, Chronic; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Myocardium; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Transforming Growth Factor beta; Ventricular Dysfunction, Left; Ventricular Remodeling

To summarized the experiences from our basic experimental and clinical research on peritoneal dialysis. In the past 16 years, peritoneal fibrosis rat models and rabbit models of peritonitis were first established successfully in our laboratory in China. Peritoneal mesothelial cells were also separated and identificated. Besides, we assessed the biocompatibility of peritoneal dialysis fluid and analyzed the molecular mechanism of peritoneal mesothelial cell injury. We demonstrated the key role of transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF) and peroxisome proliferative activated receptor-gamma (PPAR-gamma) in the pathogenesis of peritoneal fibrosis, as well as their regulation of molecular mechanism. Furthermore, we transfected the plasmids encoding TGF-beta1-shRNA or pCTGF-shRNA into peritoneal cells and tissues by nanocarrier technologies. In clinical research, the positioning of peritoneal dialysis catheters, peritoneal dialysis treatment modalities and the prevention and treatment of its complications were studied. The characteristics and mechanism of solute transport in peritoneal dialysis was also explored.

Topics: Animals; Connective Tissue Growth Factor; Fibrosis; Humans; Kidney Failure, Chronic; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Rabbits; Rats; Retrospective Studies; Tissue Adhesions; Transforming Growth Factor beta

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

The aim of this study is to examine the effect of mycophenolate mofetil (MMF) on epithelial-myofibroblast translation (EMT) in adenine-induced chronic renal failure (CRF) rat model and the role of vascular endothelial growth factor(VEGF) and inhibitor of differentiation (Id2 and Id3) in EMT in the rat kidney.. Sixty-four male Wistar rats were randomly assigned to the following groups: normal control (n = 16), CRF (n = 24) and MMF(n = 24). CRF was induced by gastric gavage of adenine (125 mg kg(-1) d(-1)) to rats for eight weeks. CRF rats were treated with MMF (15 mg kg(-1) d(-1)) as "MMF" group. The rats were sacrificed at week 2, 4, 6 and 8, respectively. Urinary protein and serum creatinine levels were measured, and the histopathologic degrees of interstitial fibrosis were evaluated in Masson-stained sections. Expressions of alpha-smooth muscle actin (alpha-SMA), transforming growth factor beta1 (TGFbeta1), VEGF and Id (Id2 and Id3) in the kidney tissue were assessed by immunohistochemistry, RT-PCR and/or Western blot methods.. The urinary protein level in MMF group was evidently lower than that in CRF group (P < 0.01), whereas no statistically significant difference was observed in serum creatinine level between the two groups. Renal interstitial fibrosis was reduced significantly with MMF treatment (P < 0.01). Expression of alpha-SMA in MMF group was lower than that in CRF rats at week 6, 8 (P < 0.01), while expression of TGFbeta1 was decreased markedly at week 2, 4, 6 (P < 0.01). The expressions of VEGF in MMF rats were increased significantly at week 6, 8 (P < 0.01), and Id2, Id3 in MMF rats were increased significantly at week 4, 6 (P < 0.05).. MMF may ameliorate chronic renal fibrosis and EMT in adenine-induced CRF rats. This effect of MMF on EMT is probably related to upregulation of VEGF, Id2 and Id3 expressions and suppressing overexpression of TGFbeta1 in renal tissue. The exact mechanism needs to be studied further.

Topics: Animals; Kidney; Kidney Failure, Chronic; Kidney Tubules; Male; Mycophenolic Acid; Rats; Rats, Wistar; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

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

Interstitial inflammation is a prominent feature associated with the severity of renal injury and progressive kidney failure. We utilized an animal model of aristolochic acid (AA)-induced nephropathy (AAN) to assess patterns of infiltration and inflammation during the evolution of tubulointerstitial damage and to relate them to the development of fibrosis.. Male Wistar rats receiving sc daily AA or vehicle were sacrificed between Days 1 and 35. Infiltrating mononuclear cells were characterized by immunohistochemistry. The kidney infiltrating T lymphocytes were phenotyped by flow cytometry. Urinary levels of Th-1/ Th-2 cytokines, of monocyte chemoattractant protein-1 and of active transforming growth factor-beta (TGF-beta) were measured. Tissue expression of phosphorylated smad 2/3 protein was used to examine the TGF-beta signalling pathway.. In AA rats, monocytes/macrophages and T lymphocytes predominantly infiltrated areas of necrotic proximal tubular cells. The coexpressions of ED1 and/or Ki-67/MHCII by infiltrating cells reflected monocyte/macrophage proliferation and their activation, respectively. The accumulation of cytotoxic T lymphocytes was attested by severe signs of CD8+ cell tubulitis. The CD8/E-cadherin costaining confirmed intrarenal homing of CD8+CD103+ cells. Urinary levels of proinflammatory cytokines and of active TGF-beta significantly increased at Days 10 and 35. An early and persistent nuclear overexpression of phosphorylated smad 2/3 protein was detected in tubular and interstitial compartments.. An early and massive interstitial inflammation characterized by activated monocytes/macrophages and cytotoxic CD8+CD103+ T lymphocytes is demonstrated for the first time during the progression of experimental AAN. The involvement in an interstitial fibrosis onset of active TGF-beta is highly suggested, at least via the psmad 2/3 intracellular signalling pathway.

Topics: Animals; Aristolochic Acids; Disease Models, Animal; Fibrosis; Kidney; Kidney Failure, Chronic; Macrophages; Male; Monocytes; Rats; Rats, Wistar; Signal Transduction; Smad2 Protein; Smad3 Protein; T-Lymphocytes; Transforming Growth Factor beta

Clinical and experimental studies have provided evidence suggesting that statins exert renoprotective effects. To investigate the mechanisms by which statins may exert renoprotection, we utilized the hypertensive Dahl salt-sensitive (DS) rat model, which manifests cardiovascular and renal injury linked to increased angiotensin II-dependent activation of NADPH oxidase and decreased nitric oxide (NO) bioavailability. DS rats given high salt diet (4% NaCl) for 10 wk exhibited hypertension [systolic blood pressure (SBP) 200 +/- 8 vs. 150 +/- 2 mmHg in normal salt diet (0.5% NaCl), P < 0.05], glomerulosclerosis, and proteinuria (158%). This was associated with increased renal oxidative stress demonstrated by urinary 8-F(2alpha)-isoprostane excretion and NADPH oxidase activity, increased protein expression of transforming growth factor (TGF)-beta (63%) and fibronectin (181%), increased mRNA expression of the proinflammatory molecules monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized LDL receptor-1 (LOX-1), as well as downregulation of endothelial NO synthase (eNOS) activity (-44%) and protein expression. Return to normal salt had no effect on SBP or any of the measured parameters. Atorvastatin (30 mg.kg(-1).day(-1)) significantly attenuated proteinuria and glomerulosclerosis and normalized renal oxidative stress, TGF-beta1, fibronectin, MCP-1 and LOX-1 expression, and eNOS activity and expression. Atorvastatin-treated rats showed a modest reduction in SBP that remained in the hypertensive range (174 +/- 8 mmHg). Atorvastatin combined with removal of high salt normalized SBP and proteinuria. These findings suggest that statins mitigate hypertensive renal injury by restoring the balance among NO, TGF-beta1, and oxidative stress and explain the added renoprotective effects observed in clinical studies using statins in addition to inhibitors of the renin-angiotensin system.

Topics: Animals; Atorvastatin; Biological Availability; Blood Pressure; Chemokine CCL2; Fibronectins; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney; Kidney Failure, Chronic; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Oxidative Stress; Proteinuria; Pyrroles; Rats; Rats, Inbred Dahl; RNA, Messenger; Scavenger Receptors, Class E; Transforming Growth Factor beta

The hallmark of progressive chronic kidney disease is the deposition of extracellular matrix proteins and tubulointerstitial fibrosis. Integrins mediate cell-extracellular matrix interaction and may play a role tubular epithelial injury. Murine primary tubular epithelial cells (TECs) express alpha(5)-integrin, a fibroblast marker and the natural receptor for fibronectin. Microscopy localized alpha(5)-integrin on E-cadherin-positive cells, confirming epithelial expression. The expression of alpha(5)-integrin increased in TECs grown on fibronectin and occurred in parallel with an upregulation of alpha-smooth muscle actin (alphaSMA), a marker of epithelial-mesenchymal transition (EMT). Exposure of TECs to transforming growth factor (TGF)-beta also increased TEC alpha(5)-integrin expression in association with alphaSMA and EMT. Knock-down of alpha5-integrin expression with short interfering RNA attenuated the TGF-beta induction of alphaSMA but did not alter morphologic EMT. Rather, alpha5-integrin was necessary for epithelial cell migration on fibronectin but not type IV collagen during cell spreading and epithelial wound healing in vitro. Immunohistochemistry revealed basolateral tubular epithelial alpha(5)-integrin expression in mouse kidneys after unilateral ureteric obstruction but not in contralateral control kidneys. In patient biopsies of nondiabetic kidney disease, alpha(5)-integrin expression was increased significantly in the renal interstitium. Focal basolateral staining was also detected in injured, but not in normal, tubular epithelium. In summary, these data show that TECs are induced to express alpha(5)-integrin during EMT and tubular epithelial injury in vitro and in vivo. These results increase our understanding of the biology of integrins during EMT and tubular injury in chronic kidney disease.

Topics: Animals; Cell Movement; Cells, Cultured; Epithelium; Gene Expression Regulation; Humans; Integrin alpha5; Kidney Failure, Chronic; Kidney Tubules; Mice; Mice, Inbred C57BL; Transforming Growth Factor beta; Ureteral Obstruction; Wound Healing

Renal fibrosis is a hallmark of end-stage renal diseases and of chronic allograft nephropathy (CAN). Rapamycin, besides its action through blockade of lymphocyte proliferation, also has antiproliferative, antiviral, and antitumor actions. Its use in clinical in patients with CAN has recently been advocated.. Our goal was to evaluate the effect of rapamycin in an established model of renal fibrosis, unilateral ureteral obstruction.. C57BL/6 mice were divided into two groups, treated or not with daily doses of rapamycin (0.2 mg/kg) beginning on day-1. The obstruction was performed as day 0. Blood and kidney tissues were collected at 1, 4, 7, and 14 days after the surgery to quantify bone morphogenic protein (BMP)-7 and transforming growth factor (TGF)-beta mRNA by real time PCR.. Daily treatment with rapamycin caused a significant reduction in serum creatinine at day 1 (0.57 +/- 0.03 vs 0.95 +/- 0.15 mg/dL, P = .002) and at day 14 (0.56 +/- 0.04 vs 0.73 +/- 0.07 mg/dL, P = .040). This profile was corroborated by histological morphometric analyses showing less fibrosis at day 14. However, rapamycin surprisingly induced an upregulation of TGF-beta at day 4 (3.05 +/- 0.46 vs 1.85 +/- 0.41, P = .006) and at day 7 (6.33 +/- 0.55 vs 4.97 +/- 0.38, P = .024) with a reduced expression by day 14 (4.03 +/- 1.07 vs 7.89 +/- 0.83, P < .001). Surprisingly, rapamycin also promoted an increment in BMP-7, completely reversing the ratio of TGF-beta to BMP-7, allowing a more protective phenotype.. Rapamycin slightly ameliorated the renal dysfunction and, at later time points, induced less fibrosis and less decrease in the TGF-beta to BMP-7 ratio.

Topics: Animals; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Creatinine; Disease Models, Animal; Disease Progression; Fibrosis; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Male; Mice; Mice, Inbred C57BL; RNA, Messenger; Sirolimus; Transforming Growth Factor beta

End-stage renal disease has been associated with an inflammatory state. TGF-beta plays a critical role in antiinflammation counteracting inflammatory cytokines, wound healing, and tissue repair. We, therefore, speculated the protective role of TGF-beta in renal inflammation rather than inducing fibrosis. Three polymorphisms of TGF-beta (713-8delC), i.e., C deletion in intron sequence 8 base prior to exon-5 by PCR-RFLP and codon-10, Leu/Pro, and codon-25, Arg/Pro by Amplification Refractory Mutation System (ARMS-PCR) techniques were genotyped in 228 end-stage renal disease (ESRD) patients and 180 controls. Linkage disequilibrium (LD) and haplotype analysis was performed by Arlequin software. Our data showed positive association between codon-10 polymorphism and ESRD risk (P < 0.001; OR 4.845, 95% CI 2.57-9.11 for Pro/Pro). However, genotype frequencies were comparable in patients and controls for 713-8delC, while in the case of codon-25, a trend of higher frequency of Pro/Pro genotype (16.2% versus 10.0%) was observed but the P-value did not reach significant (P = 0.187). Significant association of codon-10 Pro/Pro was observed in patients with glomerulonephritis (P = 0.001; OR 4.138, 95%CI 2.1-8.13). LD was found significant between codon-10 and 25 (P = 0.021). Haplotype "Pro-Pro" showed 1.8-fold higher risk for ESRD (p = 0.003; OR = 1.867, 95%CI = 1.229-2.838). A combined analysis of the effect of TGF-beta (codon-10) with C-deletion and codon-25 showed significant difference for TGF-beta(10)-TGF-beta(C-del) (P = 0.010). In conclusion, the present study suggests that low-producing genotype (Pro/Pro) of TGF-beta (codon-10) polymorphism is associated with ESRD. Haplotype analysis further suggested that "Pro-Pro" (low producer) is associated with higher risk for ESRD. Thus, high-producing genotype of TGF-beta may be beneficial and may play a potential role in the resolution of renal inflammation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Codon; Female; Genotype; Haplotypes; Humans; Kidney Failure, Chronic; Linkage Disequilibrium; Male; Middle Aged; Nephritis; Polymorphism, Genetic; Proline; Risk; Transforming Growth Factor beta

Topics: Adolescent; Glycogen Storage Disease Type I; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Kidney Tubules; Living Donors; Male; Perioperative Care; Peritoneal Dialysis; Transforming Growth Factor beta

Topics: Animals; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Disease Models, Animal; Humans; Kidney Failure, Chronic; Kidney Function Tests; Mice; Renal Dialysis; Risk Factors; Sensitivity and Specificity; Severity of Illness Index; Transforming Growth Factor beta

Multipotent mesenchymal stem or stromal cells (MSC) have shown to improve outcome of acute renal injury models, but whether MSC can delay renal failure in chronic kidney disease is not known. We injected primary MSC or saline into mice that lack the alpha3-chain of type IV collagen (COL4A3), a model of chronic kidney disease with close similarities to human Alport disease. Weekly injections of MSC from week 6 to 10 of life prevented the loss of peritubular capillaries and reduced markers of renal fibrosis, that is, interstitial volume, numbers of smooth muscle actin-positive interstitial cells, and interstitial collagen deposits as compared to saline-injected COL4A3-deficient mice. However, renal function, that is, blood urea nitrogen, creatinine levels, proteinuria as well as survival of COL4A3-deficient mice were not affected by MSC injections. Although MSC were found to localize to kidneys of COL4A3-deficient mice after injection, differentiation into renal cells was not detected. However, MSC expressed growth factors, that is, vascular endothelial growth factor (VEGF) and bone morphogenetic protein-7 under basal culture conditions. In fact, VEGF mRNA levels were increased in kidneys of MSC-injected COL4A3-deficient mice and MSC supernatants enhance endothelial cell proliferation in vitro. Thus, weekly injections with MSC prevent loss of peritubular capillaries possibly owing to local production of growth factors rather than by differentiation into renal cells. The maintenance of interstitial vasculature is associated with less interstitial fibrosis but, is insufficient to delay renal failure and survival of COL4A3-deficient mice.

Topics: Animals; Autoantigens; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Cell Movement; Cell Proliferation; Collagen Type IV; Disease Progression; Endothelial Cells; Female; Fibrosis; Kidney; Kidney Failure, Chronic; Mesenchymal Stem Cells; Mice; Mice, Mutant Strains; Multipotent Stem Cells; RNA, Messenger; Stem Cell Transplantation; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

A heterozygous mutation in autosomal Alport genes COL4A3 and COL4A4 can be found in 20 to 50% of individuals with familial benign hematuria and diffuse glomerular basement membrane thinning (thin basement membrane nephropathy [TBMN]). Approximately 1% of humans are heterozygous carriers of mutations in the autosomal Alport genes and at risk for developing renal failure as a result of TBMN. The incidence and pathogenesis of renal failure in heterozygous COL4A3/4 mutation carriers is still unclear and was examined further in this study using COL4A3 knockout mice. In heterozygous COL4A3(+/-) mice lifespan, hematuria and renal function (serum urea and proteinuria) were monitored during a period of 3 yr, and renal tissue was examined by light and electron microscopy, immunohistochemistry, and Western blot. Lifespan of COL4A3(+/-) mice was found to be significantly shorter than in healthy controls (21.7 versus 30.3 mo). Persistent glomerular hematuria was detected starting in week 9; proteinuria of > 0.1 g/L started after 3 mo of life and increased to > 3 g/L after 24 mo. The glomerular basement membrane was significantly thinned (167 versus 200 nm in wild type) in 30-wk-old mice, coinciding with focal glomerulosclerosis, tubulointerstitial fibrosis, and increased levels of TGF-beta and connective tissue growth factor. The renal phenotype in COL4A3(+/-) mice resembled the clinical and histopathologic phenotype of human cases of TBMN with concomitant progression to chronic renal failure. Therefore, the COL4A3(+/-) mouse model will help in the understanding of the pathogenesis of TBMN in humans and in the evaluation of potential therapies.

Topics: Aging; Animals; Collagen Type IV; Disease Models, Animal; Extracellular Matrix; Glomerular Basement Membrane; Glomerulonephritis, Membranous; Kidney; Kidney Failure, Chronic; Longevity; Mice; Mice, Transgenic; Nephritis, Hereditary; Phenotype; Transforming Growth Factor beta; Transforming Growth Factor beta1

This study was performed to assess the mRNA levels in skeletal muscle of maintenance hemodialysis (MHD) patients. Fifty-one sedentary MHD patients and 21 sedentary normal adults of similar age, gender distribution, and racial/ethnic mix as the patients were examined. The subjects had needle muscle biopsy to measure mRNA levels. They were assessed in right vastus lateralis muscle for insulinlike growth factor I (IGF-IEa and IGF-IEc), IGF-II, the IGF-I receptor, the IGF-II receptor, and myostatin. mRNA was measured by real-time polymerase chain reaction amplification of reverse transcribed cDNA. The results showed that in the MHD patients, as compared with the normal control patients, skeletal muscle mRNA levels for IGF-IEa, IGF-II, and the IGF-I receptor were significantly reduced, whereas mRNA for IGF-IEc, IGF-II receptor, and myostatin were not different than normal. We conclude that sedentary MHD patients show reductions in mRNA levels in the right vastus lateralis muscle for certain growth factor proteins, notably IGF-IEa, IGF-II, and the IGF-I receptor. These abnormalities may contribute to the sarcopenia and impaired endurance capacity, strength, and physical performance that occur in MHD patients.

Topics: Adult; Ethnicity; Female; Growth Substances; Humans; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Kidney Failure, Chronic; Male; Middle Aged; Muscle Proteins; Muscle, Skeletal; Myostatin; Physical Endurance; Receptor, IGF Type 1; Receptor, IGF Type 2; Renal Dialysis; RNA, Messenger; Transforming Growth Factor beta

Resistance to growth hormone (GH)-induced insulin-like growth factor-1 (IGF-1) gene expression contributes to uremic muscle wasting. Since exercise stimulates muscle IGF-1 expression independent of GH, we tested whether work overload (WO) could increase skeletal muscle IGF-1 expression in uremia and thus bypass the defective GH action. Furthermore, to provide insight into the mechanism of uremic wasting and the response to exercise we examined myostatin expression. Unilateral plantaris muscle WO was initiated in uremic and pairfed (PF) normal rats by ablation of a gastrocnemius tendon and adjoining part of this muscle with the contralateral plantaris as a control. Some rats were GH treated for 7 days. WO led to similar gains in plantaris weight in both groups and corrected the uremic muscle atrophy. GH increased plantaris IGF-1 mRNA >twofold in PF rats but the response in uremia was severely attenuated. WO increased the IGF-1 mRNA levels significantly in both uremic and PF groups, albeit less brisk in uremia; however, after 7 days IGF-1 mRNA levels were elevated similarly, >2-fold, in both groups. In the atrophied uremic plantaris muscle basal myostatin mRNA levels were increased significantly and normalized after an increase in WO suggesting a myostatin role in the wasting process. In the hypertrophied uremic left ventricle the basal myostatin mRNA levels were reduced and likely favor the cardiac hypertrophy. Together the findings provide insight into the mechanisms of skeletal muscle wasting in uremia and the hypertrophic response to exercise, and suggest that alterations in the balance between IGF-1 and myostatin play an important role in these processes.

Topics: Animals; Blood Urea Nitrogen; Body Weight; Creatinine; Drug Resistance; Gene Expression; Growth Hormone; Heart; Hypertrophy; Hypertrophy, Left Ventricular; Insulin-Like Growth Factor I; Kidney Failure, Chronic; Male; Muscle, Skeletal; Muscular Atrophy; Myostatin; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transforming Growth Factor beta; Uremia

In two independent and separate studies, we have shown that renal injury and chronic kidney disease (CKD) directly inhibit skeletal anabolism, and that stimulation of bone formation decreased the serum phosphate. In the first study, the serum Ca PO(4), parathyroid hormone (PTH), and calcitriol were maintained normal after renal ablation in mice, and even mild renal injury equivalent to stage 3 CKD decreased bone formation rates. More recently, these observations were rediscovered in low-density lipoprotein receptor null (LDLR-/-) mice fed high-fat/cholesterol diets, a model of the metabolic syndrome (hypertension, obesity, dyslipidemia and insulin resistance). We demonstrated that these mice have vascular calcification (VC) of both the intimal atherosclerotic type and medial calcification. We have also shown that VC is made worse by CKD and ameliorated by bone morphogenetic protein-7 (BMP-7). The finding that high-fat fed LDLR-/- animals with CKD had hyperphosphatemia which was prevented in BMP-7-treated animals lead us to examine the skeletons of these mice. It was found that significant reductions in bone formation rates were associated with high-fat feeding, and superimposing CKD resulted in the adynamic bone disorder (ABD), while VC was made worse. The effect of CKD to decrease skeletal anabolism (decreased bone formation rates and reduced number of bone modelling units) occurred despite secondary hyperparathyroidism. The BMP-7 treatment corrected the ABD and hyperphosphatemia, owing to BMP-7-driven stimulation of skeletal phosphate deposition reducing plasma phosphate and thereby removing a major stimulus to VC. A pathological link between abnormal bone mineralization and VC through the serum phosphorus was demonstrated by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. Thus, in the metabolic syndrome with CKD, a reduction in bone forming potential of osteogenic cells leads to the ABD producing hyperphosphatemia and VC, processes ameliorated by BMP-7, in part through increased bone formation and skeletal deposition of phosphate and in part through direct actions on vascular smooth muscle cells. We have demonstrated that the processes leading to vascular calcification begin with even mild levels of renal injury affecting the skeleton before demonstrable hyperphosphatemia and that they are preventable and treatable. Therefore, early intervention in the skeletal disorder associated wi

Topics: Animals; Bone and Bones; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcinosis; Cartilage; Cell Differentiation; Chronic Kidney Disease-Mineral and Bone Disorder; Humans; Kidney; Kidney Failure, Chronic; Mice; Osteoblasts; Osteogenesis; Phosphates; Transforming Growth Factor beta; Vascular Diseases

To probe into the mechanisms of thread implantation at Zusanli(ST 36) and Chinese herbs in treatment of chronic renal failure(CRF).. CRF rat model was made by Platt subtotal nephrectomy. They were divided into 5 groups, sham operation group, model group, Chinese herbs group, thread implantation group and thread implantation plus Chinese herbs group. After treatment of 8 weeks, serum parathyroid hormone (PHT), transforming growth factor beta1 (TGF-beta1) expression in residual renal cells, malondialdehyde(MDA) content in the residual renal tissue, serum urea nitrogen(BUN) and creatinine(Scr), protein in urine and pathological changes were investigated.. The above indexes after treatment by thread implantation at acupoint, Chinese herbs, and acupoint thread implantation plus Chinese herbs showed begin reversion, especially, the most obviously improvement in the acupoint thread implantation plus Chinese herbs treatment group.. The mechanism of acupoint thread implantation and Chinese herbs in improvement of CRF is related with decrease of PTH, inhibition of TGF-beta1 expression, decrease of MDA content and resisting lesion of renal fibrosis.

Topics: Acupuncture Points; Animals; Drugs, Chinese Herbal; Kidney Failure, Chronic; Male; Parathyroid Hormone; Rats; Rats, Wistar; Transforming Growth Factor beta; Transforming Growth Factor beta1

Studies of mechanisms of disease regulation by CD4+CD25+ regulatory T cells (Treg) have been focused on their interaction with effector T cells; however, the possibility that regulation might involve noncognate cells has not been explored in detail. This study investigated the effect of CD4+CD25+ Treg on macrophage proinflammatory properties and phenotype in vitro and found that they modulate macrophages by inhibiting their activation, leading to reduced proinflammatory cytokine production and a downregulated effector phenotype. For testing the in vivo significance of this effect, CD4+CD25+ T cells that expressed high levels of Foxp3 were reconstituted into SCID mice after induction of Adriamycin nephropathy, a noncognate model of chronic renal disease. CD4+CD25+ T cells significantly reduced glomerular and interstitial injury. In addition, there was a significant fall in the number of macrophages in both the glomeruli and interstitium of SCID mice that were reconstituted with Treg as compared with the Adriamycin alone group. Blockade of TGF-beta using neutralizing antibodies significantly impaired the protective effect of Treg. These findings delineate a TGF-beta-dependent Treg-macrophage inhibitory interaction that can explain cognate-independent protection by Treg.

Topics: Animals; CD4 Antigens; Cytokines; Disease Models, Animal; Doxorubicin; Flow Cytometry; Forkhead Transcription Factors; Immunoenzyme Techniques; Interleukin-2 Receptor alpha Subunit; Kidney; Kidney Failure, Chronic; Macrophages; Male; Mice; Mice, Inbred BALB C; Mice, SCID; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Topics: Endothelium, Vascular; Humans; Infusions, Intravenous; Iron; Kidney Failure, Chronic; Transforming Growth Factor beta; Transforming Growth Factor beta1

The degree of renal scarring in kidney biopsy is an important prognostic factor in patients with chronic kidney diseases. We hypothesize that gene expression in the urinary sediment reflects the degree of renal damage.. We studied 29 patients with chronic kidney disease who underwent kidney biopsy (12 immunoglobulin-A nephropathy and 17 glomerulosclerosis) and 10 healthy controls. The mRNA expressions of a panel of target genes in urinary sediment were measured by real-time quantitative polymerase chain reaction. The results were compared with the degree of histological damage and renal function decline.. There were significant differences in the urinary expression of transforming growth factor-beta (TGF-beta), monocyte chemotactic protein-1 (MCP-1) and collagen IV between disease groups and controls. Urinary TGF-beta mRNA expression correlated significantly with estimated glomerular filtration rate (r = -0.412, P = 0.029) and the degree of tubulointerstitial scarring (r = 0.418, P = 0.024). Urinary MCP-1 expression correlated with the degree of glomerulosclerosis (r = 0.450, P = 0.014), but not tubulointerstitial scarring. Urinary MCP-1 expression correlated with its corresponding level by enzyme-linked immunosorbent assay (ELISA) (r = 0.650, P<0.001), but TGF-beta expression did not correlate with its ELISA level. Urinary TGF-beta gene expression correlated with its intra-renal expression in glomeruli (r = 0.701, P<0.001) and tubulointerstitium (r = 0.573, P = 0.001) by immunohistochemistry, while urinary MCP-1 gene expression correlated with its staining in glomeruli (r = 0.576, P = 0.001) but not tubulointerstitium. After 12 months, there was a significant inverse correlation between the rate of renal function decline and urinary expression of connective tissue growth factor (r = -0.471, P = 0.010) and collagen I (r = -0.399, P = 0.032), but not TGF-beta or MCP-1.. Amongst the target genes examined, the mRNA expression of TGF-beta in urinary sediment correlated with renal function, the degree of histological damage and intra-renal level in patients with chronic kidney diseases. Measurement of TGF-beta mRNA expression in urine may be a useful non-invasive tool for assessing the severity of renal damage in patients with chronic kidney diseases.

Topics: Adult; Aged; Base Sequence; Biomarkers; Case-Control Studies; Chemokine CCL2; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Humans; Kidney Failure, Chronic; Male; Middle Aged; Molecular Sequence Data; Probability; Prognosis; Reference Values; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sensitivity and Specificity; Severity of Illness Index; Transforming Growth Factor beta

The aim of this study was to define the severe deficits of protein glycation adduct clearance in chronic renal failure and elimination in peritoneal dialysis (PD) and hemodialysis (HD) therapy using a liquid chromatography-triple quadrupole mass spectrometric detection method. Physiologic proteolysis of proteins damaged by glycation, oxidation, and nitration forms protein glycation, oxidation, and nitration free adducts that are released into plasma for urinary excretion. Inefficient elimination of these free adducts in uremia may lead to their accumulation. Patients with mild uremic chronic renal failure had plasma glycation free adduct concentrations increased up to five-fold associated with a decline in renal clearance. In patients with ESRD, plasma glycation free adducts were increased up to 18-fold on PD and up to 40-fold on HD. Glycation free adduct concentrations in peritoneal dialysate increased over 2- to 12-h dwell time, exceeding the plasma levels markedly. Plasma glycation free adducts equilibrated rapidly with dialysate of HD patients, with both plasma and dialysate concentrations decreasing during a 4-h dialysis session. It is concluded that there are severe deficits of protein glycation free adduct clearance in chronic renal failure and in ESRD on PD and HD therapy.

Topics: Adult; Aged; Chemokine CCL2; Dialysis Solutions; Female; Glycation End Products, Advanced; Glycosylation; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nitrogen; Oxidation-Reduction; Peritoneal Dialysis; Renal Dialysis; Severity of Illness Index; Transforming Growth Factor beta; Uremia

Immunoincompetence is a profound problem in end-stage renal failure patients undergoing hemodialysis, and chronic inflammation with altered serum levels of inflammation markers has been reported. Gene expression patterns have had little relevance for leukocyte research so far because of limitations in transcript levels and stability. Using a new stimulation system we induced the expression of immune-relevant transcripts in whole blood preparations ex vivo and stabilized transcript levels by preventing RNA degradation and uncontrolled gene induction. Using quantitative real-time PCR we could show that basal TGF-beta mRNA expression is about 2-fold decreased in end-stage renal failure patients, while expression of TNF-alpha becomes 2-fold increased, further doubling during hemodialysis. By short term stimulation with phytohemagglutinin (PHA) for 2 h we tested for the immune competence of peripheral blood leukocytes and demonstrated that hemodialysis decreases TNF-alpha-mediated immune responsiveness more than 3-fold. This study shows by induction and stabilization of immune-relevant transcripts that chronic inflammation and hemodialysis are crucial factors for disturbed immune competence of end-stage renal failure patients.

Topics: Adult; Biomarkers; Female; Humans; Immunocompetence; Inflammation; Kidney Failure, Chronic; Leukocytes; Male; Middle Aged; Renal Dialysis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

To characterize dynamics of changes of serum levels of TGF-beta1 and TNF-alpha in rats with cardiac fibrosis (CF) occurring during chronic renal failure (CRF), and to reveal the character pf correlations of these factors with amounts of cardiac collagen.. CRF was induced by unilateral nephrectomy and by electrocoagulation of 25% of the cortex of remnant kidney. Post-operative checkpoints were 2, 4, and 6 months. Serum TGF-beta1 and TNF-alpha levels were measured by ELISA.. CF became pronounced only at 6 months of CRF, while serum TGF-beta1 concentrations reached maximum at 4 months, i.e., at the checkpoint preceding the development of CF. Multiple regression showed cardiac collagen to correlate with both serum TGF-beta1 levels and time from the onset of CRF. Sensitivity and specificity of TGF-beta1 as serum marker of CF were 86% and 75%.

Topics: Animals; Biomarkers; Disease Models, Animal; Fibrosis; Kidney Failure, Chronic; Male; Myocardium; Rats; Sensitivity and Specificity; Time Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Associations have been described between polymorphisms of cytokine and growth factor genes and susceptibility to, or progression of, an increasing number of diseases. TGF-beta1 plays an important role in the pathogenesis of experimental and clinical glomerulosclerosis and tubulointerstitial fibrosis. In this study, single nucleotide polymorphisms (SNPs) in the TGFbeta1 gene were investigated as possible markers for the progression of chronic kidney failure (CKF). 145 Caucasian patients with CKF were screened for four TGFbeta1 SNPs: T-509C in the promoter region; Arg25Pro and Leu10Pro in exon 1 and Thr263Ile in exon 5. There were significant differences between CKF patients and controls in allele frequencies of two of the SNPs, Leu10Pro (p = 0.038) and C-509T (p = 0.02) and in haplotype distributions (p = 0.0175), indicating an association with susceptibility to CKF. We also observed a significant association between progression of CKF and homozygosity for Arg25 (odds ratio 3.77, 95% confidence interval 1.57-9.04, p = 0.002). Homozygosity for Arg25 was also associated with severity of proteinuria at diagnosis (p = 0.038), plasma TGF-beta1 protein levels (p = 0.01), and severity of glomerulosclerosis (p = 0.04). Homozygosity for -509T was associated with severity of proteinuria at diagnosis (p = 0.0017), level of renal tubular TGF-beta1 immunostaining (p = 0.0006) and with severity of renal interstitial inflammatory cellular infiltration (p = 0.01). Tubular TGF-beta1 immunostaining was significantly higher in biopsies with inflammatory cellular infiltration compared those without inflammation (p = 0.0048). There was a significant difference in haplotype distributions between CKF patients with progressive, as opposed to non-progressive disease (p = 0.0484). TGFbeta1 SNPs may be useful prognostic indicators for the progression of CKF.

Topics: Adult; Aged; Aged, 80 and over; Arginine; Case-Control Studies; Cytosine; Disease Progression; Female; Fibrosis; Gene Frequency; Genetic Predisposition to Disease; Genotype; Glomerulosclerosis, Focal Segmental; Haplotypes; Homozygote; Humans; Immunohistochemistry; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Phenotype; Polymorphism, Single Nucleotide; Proline; Severity of Illness Index; Staining and Labeling; Thymine; Transforming Growth Factor beta; Transforming Growth Factor beta1

Maintenance hemodialysis patients often display evidence for protein-energy malnutrition, inflammation, and sarcopenia. We therefore investigated whether sedentary maintenance hemodialysis patients have decreased skeletal muscle mRNA levels and muscle and serum protein concentrations of certain growth factors.. Fifty-one clinically stable maintenance hemodialysis patients (32 men and 19 women), and 21 normal adults (16 men and five women) of similar age, gender mix, racial/ethnic backgrounds, serum albumin, body composition, and level of sedentary activity were studied. Individuals underwent biopsy of the right vastus lateralis muscle, and real-time polymerase chain reaction (PCR) amplification of mRNAs for insulin-like growth factor-I (IGF-I), IGF-II, IGF-I receptor (IGF-IR), IGF-IIR, and myostatin (44 patients) was performed. Serum and muscle IGF-I and IGF-II, serum proinflammatory cytokines, and leg muscle strength, power, and fatigability were measured.. Maintenance hemodialysis patients displayed significantly reduced mRNA levels for IGF-IEa mRNA (P < 0.05), IGF-II (P < 0.001), and IGF-IR (P < 0.001), and no difference in mRNAs for IGF-IEc, IGF-IIR, or myostatin as compared to normal controls. Muscle mRNA levels, in general, followed the same pattern in male and female maintenance hemodialysis patients considered separately. In the maintenance hemodialysis patients, muscle IGF-I protein, serum IGF-II and tumor necrosis factor-alpha (TNF-alpha) were each increased, whereas serum C-reactive protein (CRP) and interleukin-6 (IL-6) were normal. Muscle strength and power, but not fatigability, were reduced in the maintenance hemodialysis patients.. In sedentary, clinically stable maintenance hemodialysis patients as compared to sedentary normal individuals, the mRNA levels for IGF-IEa, IGF-II, and the IGF-I receptor are decreased in vastus lateralis muscle. Protein levels for muscle IGF-I and serum IGF-II are increased.

Topics: Adult; Female; Humans; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Kidney Failure, Chronic; Life Style; Male; Middle Aged; Motor Activity; Muscle, Skeletal; Muscular Atrophy; Myostatin; Receptor, IGF Type 1; Receptor, IGF Type 2; Renal Dialysis; RNA, Messenger; Transforming Growth Factor beta

Dent's disease, an X-linked renal tubular disorder, is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. Dent's disease results from mutations of the voltage-gated chloride channel CLC-5.. We studied the effect of zero and high citrate diet on renal function of ClC-5 knockout mice and wild-type mice. The mice were placed in metabolic cages from which the urine was collected. Mice were sacrificed to obtain serum and tissues for analysis.. ClC-5 knockout mice fed zero or high citrate diet had significantly increased urinary calcium excretion compared with wild-type mice fed the same diets. Nine-month-old ClC-5 knockout mice on a zero citrate diet had significantly decreased glomerular filtration rate (GFR), whereas 9-month-old ClC-5 knockout mice on a high citrate diet had normal renal function. ClC-5 knockout mice fed a zero citrate diet had significantly increased tubular atrophy, interstitial fibrosis, cystic changes, and nephrocalcinosis compared to ClC-5 knockout mice fed a high citrate diet. Transforming growth factor-beta1 (TGF-beta1) was significantly increased in 9-month-old ClC-5 knockout mice on zero citrate diet compared to 9-month-old wild-type mice on the same diet.. High citrate diet preserved renal function and delayed progression of renal disease in ClC-5 knockout mice even in the apparent absence of stone formation. We conclude from this that long-term control of hypercalciuria is an important factor in preventing renal failure in these mice.

Topics: Animals; Blood Urea Nitrogen; Calcinosis; Calcium; Chloride Channels; Citrates; Creatinine; Diet; Disease Models, Animal; Glomerular Filtration Rate; Hydrogen-Ion Concentration; Kidney Calculi; Kidney Failure, Chronic; Mice; Mice, Knockout; Potassium; Sodium; Transforming Growth Factor beta; Transforming Growth Factor beta1

Changes in renal vasculature, with vascular and interstitial fibrosis, are hallmarks of progression to chronic kidney disease (CKD) stage 5. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor. Transforming growth factor-beta1 (TGF-beta1) plays a critical role in promoting extracellular matrix (ECM) deposition and fibrosis. This study investigates whether genetic polymorphisms of VEGF or TGF-beta1 are associated with (i) progressive decline in renal function in patients with glomerular disorders (cohort 1) and (ii) predisposition to CKD stage 5 in a separate group of renal transplant recipients with various primary diseases (cohort 2).. Two patient groups were studied. Cohort 1 comprised 91 patients with biopsy-proven glomerular disease who were followed-up for 5 years before categorization as either non-progressors (with stable serum creatinine or < or =30% increase over 5 years, n = 39) or progressors (requiring dialysis, transplantation or whose serum creatinine increased by >30% over 5 years, n = 52). Cohort 2 comprised 107 patients with various primary renal diseases, who had reached CKD stage 5 and undergone renal transplantation at the time of study. All patients were genotyped for the VEGF polymorphisms at positions -460 (C/T) and +405 (G/C). Linkage disequilibrium (LD) was established using EHplus. SNPHAP was used to estimate haplotype frequency and to infer haplotypes to all patients. Cohort 1 patients were genotyped for the TGF-beta1 polymorphisms at positions -800, -509, codons 10 and 25. Genotyping was performed by polymerase chain reaction-restriction length polymorphism (PCR-RFLP).. In cohort 1, there was a significant increase in frequency of the -460 VEGF CC genotype 30.8 vs 5.1%, P = 0.008; odds ratio (OR), CC vs TT 10.67, 95% confidence interval (CI), 1.94-58.72 and C allele 56.7 vs 37.2%, P = 0.009; OR 2.22, 95% CI, 1.21-4.04, in the progressor patients when compared with the non-progressors. In cohort 2, there was a significant increase in the VEGF -460 CC genotype when compared with healthy volunteers 37 vs 20.8%, P = 0.011; OR CC vs TT 1.59, 95% CI, 0.72-3.51. The -460 and +405 polymorphisms were in LD P < 0.00007. There were significant differences in diplotype (haplotype pair) frequencies in cohort 1 and 2, P = 0.018, which confirmed the importance of the -460C allele. There were no associations between the VEGF +405 or TGF-beta1 polymorphisms and progressive renal disease.. In this study, we have demonstrated an association between the VEGF -460 polymorphism and progression to CKD stage 5. The function of this polymorphism remains unclear although previous evidence suggests that promoter constructs containing this single nucleotide polymorphism (SNP) have been associated with increased activity. Clearly there is a role for TGF-beta1 in chronic kidney disease. However, this study found no associations with four TGF-beta1 polymorphisms in this cohort.

Topics: Biopsy; Disease Progression; DNA; Female; Follow-Up Studies; Genetic Markers; Genotype; Humans; Kidney Failure, Chronic; Linkage Disequilibrium; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Severity of Illness Index; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vascular Endothelial Growth Factors

We studied the effect of Vilon in rats 2, 4, and 6 months after the onset of chronic renal failure. Subcutaneous injection of Vilon significantly decreased serum concentration of transforming growth factor-beta(1) and permeability of mesenteric microvessels in rats 2 months after the onset of chronic renal failure. Our results indicate that the preparation produces a potent homeostatic effect in the early period of chronic renal failure.

Topics: Animals; Capillaries; Capillary Permeability; Dipeptides; Endothelium, Vascular; Kidney Failure, Chronic; Male; Mesenteric Artery, Inferior; Rats; Transforming Growth Factor beta

TGF-beta1 maintains homeostasis of rapidly proliferating cells, therefore is a potential tumor suppressor of non-malignant cells. Malignant transformation alters TGF-beta1 signalling pathway, turning it into a stimulator of tumor progression. We describe the case of 54 year old renal transplant patient with highly increased plasma TGF-beta1 level and planoepithelial carcinoma originating from parotid salivary gland. We discuss the role of TGF-beta1 in promotion of carcinogenesis and probable utility in prognosis of malignancy.

Topics: Carcinoma; Fatal Outcome; Glomerulonephritis; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Parotid Neoplasms; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor-beta1 (TGF-beta1) stimulates the deposition of extracellular matrix (ECM), which is a hallmark in end-stage renal disease. The importance of TGF-beta1-induced changes in protease activity in this process is not fully elucidated. TGF-beta1 up-regulates plasminogen activator inhibitor type 1 (PAI-1), which lowers matrix degradation. Our aim was to investigate the importance of PAI-1 in TGF-beta1-induced kidney disease.. TGF-beta1 transgenic mice were bred with PAI-1 gene deficient mice. The effect of PAI-1 gene knockout on TGF-beta1-induced glomerular disease was investigated by measuring morphologic changes in the glomeruli. Interstitial changes were assessed by measurement of total collagen content and expression and localization of ECM components. Finally, protease activity was evaluated by plasmin activity measurement and by gel and in situ gelatin zymography.. TGF-beta1 elevated PAI-1 expression fourfold. PAI-1 gene deficiency attenuated the TGF-beta1-induced mesangial expansion and basement membrane thickening. Furthermore, PAI-1 knockout diminished collagen accumulation in TGF-beta1-positive mice. The expression of both collagen type I and III were reduced. Interestingly, no difference in protease activity could be ascertained as cause of the decreased ECM accumulation.. We show that PAI-1 gene deficiency attenuates TGF-beta1-induced kidney disease, decreasing both glomerular and interstitial ECM deposition. Thus, PAI-1 mediates some of the biological effects of TGF-beta1 in vivo. However, we could not find evidence supporting the notion that the effect was mediated through increased protease activity.

Topics: Animals; Basement Membrane; Body Weight; Collagen; Extracellular Matrix; Extracellular Matrix Proteins; Fibrinolysin; Fibronectins; Kidney Failure, Chronic; Kidney Glomerulus; Macrophages; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Organ Size; Plasminogen Activator Inhibitor 1; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

Cytokine transforming growth factor (TGF) is involved in regulation of tissue repair after injury. More recently, TGF-beta1 codon 10 gene polymorphism has been shown to be associated with circulating TGF-beta levels. We tested whether TGF-beta1 genotype polymorphism was predictive of renal allograft function decline.. The study population consisted of 129 consecutive cadaveric or living related renal transplant recipients at our center between 1985 and 2001. The recipient TGF-beta1 genotype polymorphism was determined from peripheral blood leucocytes DNA. The primary endpoint was rate of glomerular filtration rate decline between the first year and the third year of transplant.. Baseline glomerular filtration rate as estimated by MDRD study equation at 1 year measured 50+/-17 mL/min/1.73 m2. At the end of the 3-year follow-up period, 52 patients (40%) experienced biopsy-confirmed acute rejections. Frequency and severity of allograft rejection did not differ with TGF-beta genotypes. However, the decline in glomerular filtration rate was significantly greater in Leu/Leu (TT) than Leu/Pro (CT) recipients, 6.3+/-16.9 mL/min/1.73 m2 versus 0.1+/-10.2 mL/min/1.73 m2, p=0.04.. Our results demonstrate that recipient TGF-beta1 codon 10 Leu/Leu homozygosity is a potential risk factor of kidney allograft function decline.

Topics: Adolescent; Adult; Cadaver; Cohort Studies; Female; Gene Expression Regulation; Genetic Markers; Glomerular Filtration Rate; Graft Rejection; Graft Survival; History, 16th Century; Hong Kong; Humans; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Polymorphism, Genetic; Predictive Value of Tests; Probability; Prognosis; Retrospective Studies; Risk Assessment; RNA, Messenger; Sensitivity and Specificity; Severity of Illness Index; Statistics, Nonparametric; Survival Rate; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transplantation, Homologous; Treatment Outcome

Transforming growth factor-beta1 (TGF-beta1), an inflammatory cytokine, plays a role in tissue fibrosis, such as glomerular sclerosis and tubulointerstitial fibrosis of the kidneys. In the present study, the urinary TGF-beta1 level of cats diagnosed with chronic renal failure (CRF) was measured to investigate its relationship to the pathogenesis of feline CRF. Urinary TGF-beta1 levels (TGF-beta1/creatinine ratio) were significantly increased compared with healthy controls, whereas serum levels of TGF-beta1 were not. These results indicate that TGF-beta1 is expressed in the kidneys of CRF cats, and that it was reflected in the urinary TGF-beta1 level. Therefore, TGF-beta1 may play a role in feline CRF, and urinary TGF-beta1 could be used as a clinical marker for renal fibrosis.

Topics: Animals; Biomarkers; Cat Diseases; Cats; Creatine; Kidney; Kidney Failure, Chronic; Transforming Growth Factor beta; Transforming Growth Factor beta1

Diabetic nephropathy is now the leading cause of end-stage renal diseases, and glomerular sclerotic injury is an initial event that provokes renal dysfunction during processes of diabetes-linked kidney disease. Growing evidence shows that transforming growth factor-beta 1 (TGF-beta 1) plays a key role in this process, especially in eliciting hypertrophy and matrix overaccumulation. Thus it is important to find a ligand system to antagonize the TGF-beta 1-mediated pathogenesis under high-glucose conditions. Herein, we provide evidence that hepatocyte growth factor (HGF) targets mesangial cells, suppresses TGF-beta 1 production, and minimizes glomerular sclerotic changes, using streptozotocin-induced diabetic mice. In our murine model, glomerular sclerogenesis (such as tuft area expansion and collagen deposition) progressed between 6 and 10 wk after the induction of hyperglycemia, during a natural course of diabetic disease. Glomerular HGF expression levels in the diabetic kidney transiently increased but then declined below a basal level, with manifestation of glomerular sclerogenesis. When anti-HGF IgG was injected into mice for 2 wk (i.e., from weeks 4 to 6 after onset of hyperglycemia), these glomerular changes were significantly aggravated. When recombinant HGF was injected into the mice for 4 wk (i.e., between 6 and 10 wk following streptozotocin treatment), the progression of glomerular hypertrophy and sclerosis was almost completely inhibited, even though glucose levels remained unchanged (>500 mg/dl). Even more important, HGF repressed TGF-beta 1 production in glomerular mesangial cells even under hyperglycemic conditions both in vitro and in vivo. Consequently, not only albuminuria but also tubulointerstitial fibrogenesis were attenuated by HGF. Overall, HGF therapy inhibited the onset of renal dysfunction in the diabetic mice. On the basis of these findings, we wish to emphasize that HGF plays physiological and therapeutic roles in blocking renal fibrogenesis during a course of diabetic nephropathy.

Topics: Actins; Albuminuria; Animals; Cells, Cultured; Collagen Type IV; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Female; Gene Expression; Glomerular Mesangium; Hepatocyte Growth Factor; Kidney Failure, Chronic; Mice; Mice, Inbred C57BL; Transforming Growth Factor beta; Transforming Growth Factor beta1

Although short-term treatment with anti-transforming growth factor-beta (TGF-beta) antibody (alphaT) has been shown to prevent early glomerular lesions, its long-term effects and molecular mechanisms, including intracellular signaling, remain poorly understood. We examined whether alphaT treatment induces prevention of renal insufficiency and fibrosis, and affects the TGF-beta/Smad signaling pathway in rats with chronic progressive anti-thymocyte serum (ATS) nephritis induced by repeated ATS injections on days 0 and 7.. Nephritic and non-nephritic rats were treated with either alphaT or control immunoglobulin (Ig)G twice weekly for 4 weeks from days 7 to 35 (each group, N= 21). Renal lesions and cortical expression of TGF-beta1, TGF-beta2, TGF-beta3, type II TGF-beta receptor (TbetaRII), Smads, type I collagen, and plasminogen activator inhibitor-1 were examined by immunohistochemistry, Western blot, and/or real-time reverse transcription polymerase chain reaction (RT-PCR). The binding of Smad3 in renal cortical cell nuclei to the Smad-binding element (SBE) was investigated by the electrophoretic mobility shift assay.. Nephritic rats developed heavy proteinuria, renal insufficiency, and increased extracellular matrix deposition resulting in renal fibrosis. Cortical expression levels of TGF-beta1, TGF-beta2, TbetaRII, and Smad2, but not TGF-beta3, Smad3, and Smad4 were increased. Expression and preferential localization of phosphorylated Smad2/3 in the glomerular and tubular cell nuclei, and Smad3-SBE complex-forming activity were also increased. Four-week alphaT treatment resulted in marked amelioration of chronic progressive ATS nephritis at 8 weeks.. In chronic progressive ATS nephritis, the TGF-beta/Smad signaling was up-regulated. TGF-beta blockade by alphaT suppressed the progression of renal scarring, at least in part, via inhibition of activated TGF-beta/Smad signaling.

Topics: Animals; Body Weight; Collagen; Collagen Type I; DNA-Binding Proteins; Down-Regulation; Female; Glomerulonephritis; Hydroxyproline; Immunoglobulin G; Immunotherapy; Kidney Cortex; Kidney Failure, Chronic; Male; Plasminogen Activator Inhibitor 1; Proteinuria; Rats; Rats, Wistar; RNA, Messenger; Sheep; Signal Transduction; Smad2 Protein; Smad3 Protein; Trans-Activators; Transforming Growth Factor beta

An adynamic bone disorder (ABD) is an important complication of chronic kidney disease (CKD) of unknown etiology for which there is no adequate treatment. Reported is an animal model of ablative CKD complicated by an ABD characterized by the absence of secondary hyperparathyroidism and its successful treatment with a skeletal anabolic factor, bone morphogenetic protein-7 (BMP-7). Adult mice were subjected to electrocautery of the right kidney followed by left nephrectomy. Animals were randomized into groups fed normal chow or fed low-phosphate chow supplemented with calcitriol to maintain normophosphatemia in CKD. All groups were maintained on the regimens for 12 wk. Hyperphosphatemia, secondary hyperparathyroidism, and a mild osteodystrophy developed in the CKD/chow-fed group, as expected. When dietary phosphorus was restricted and calcitriol was administered in the CKD low-phosphate/calcitriol group (ABD), Ca, PO(4), and parathyroid hormone levels were maintained normal. A significant ABD developed in the ABD group characterized by significant depressions in osteoblast number, perimeters, bone formation rates, and mineral apposition rates when compared with the sham-operated, chow-fed group. The abnormal skeletal histomorphometry was reversed by BMP-7 therapy to normal values and significantly improved from the ABD group (P < 0.05). The sham-operated low-phosphate/calcitriol-fed control group and the CKD low-phosphate/calcitriol/BMP-7 groups had reduced phosphate levels compared with the other groups (P < 0.05). ABD produced in mice with CKD in the absence of hyperparathyroidism was successfully reversed with a bone anabolic, BMP-7, associated with a reduction in plasma phosphorus.

Topics: Animals; Bone Diseases; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Kidney Failure, Chronic; Male; Mice; Mice, Inbred C57BL; Nephrectomy; Remission Induction; Transforming Growth Factor beta

The contact of chronic hemodialysis patients' blood with components of extracorporeal circulation leads to mobilization of several systemic reactions. The purpose of this study was to determine the activity of transforming growth factor (TGF-beta1) and platelet derived growth factor (PDGF) in serum of patients on long-term hemodialysis program and to compare these results with ones obtained in healthy volunteers. Twenty-five patients on dialysis carried out on polysulfone membrane dialyzer, and 16 patients on dialysis with the used of cuprophan membrane dialyzer on long-term hemodialysis program participated in the study. TGF-beta1 level in serum of healthy volunteers (12.06 +/- 7.56 ng/mL) was lower than in serum of patients dialyzed on polysulfone membrane dialyzers (26.56 +/- 14.83 ng/mL). Differences in PDGF concentrations in serum of control group and hemodialyzed patients were not statistically significant. The strong correlation between TGF-beta1 and PDGF in serum of both studied groups of patients was demonstrated.

Topics: Adult; Female; Humans; Kidney Failure, Chronic; Male; Membranes, Artificial; Middle Aged; Platelet-Derived Growth Factor; Renal Dialysis; Transforming Growth Factor beta; Transforming Growth Factor beta1

Tissue kallikrein regulates blood circulation. Low urinary kallikrein excretion was associated with hypertension and renal disease in blacks. The polymorphic KLK1 promoter includes -130 GN coupled with multiple single base substitutions. The -130 G12 allele in the KLK1 promoter was associated with lower transcriptional activity and hypertensive end-stage renal disease (ESRD) in blacks. Transforming growth factor-beta1 (TGF-beta1) regulates matrix production, and induces fibrosis in a variety of tissues. High circulating TGF-beta1 levels mediating renal fibrosis and loss of function in transgenic mice. The -509 T allele in the TGF-beta1 promoter showed marginally higher transcriptional activity, and was associated with increased TGF-beta1 production in humans. The aim of this study was to investigate whether the tissue KLK1 promoter and TGF-beta1 polymorphism are involved in primary vesicoureteric reflux (VUR) with renal progression in children.. Seventy-four primary VUR children were studied with regular annual follow-up for more than 18 years, all of them more than grade II (diagnosed by voiding cystourethroradiography). All of them were born before 1984. Patients were classified into two groups according to the renal function with progressive deterioration or not. Patients with baseline creatinine clearance (CCr) less than 25 mL/min were defined as having chronic renal insufficiency (CRI). The TGF-beta1 -509 T-C polymorphism was analyzed by Bsu36I restriction fragment length polymorphism (RFLP)-polymerase chain reaction (PCR). In KLK1 promoter, the -130 GN length polymorphism and multiple single base substitutions were analyzed by electrophoresis of fluoresced PCR products in sequencing gels, single strand conformation polymorphism (SSCP), allele-specific PCR, and DNA sequencing. Patients' TGF-beta1 and KLK1 promoter polymorphisms were evaluated for association with VUR susceptibility and progression in Taiwanese children. Annual echocardiography study was used to evaluate left ventricular mass index (LVMI).. Four alleles were identified in the complex KLK1 promoter: A (-130 G10), B (-130 G2CG7), H (-130 G11), and K (-130 G12). The polymorphic KLK1 promoter showed no association with VUR susceptibility. However, the frequency distribution of KLK1 promoter among VUR patients with or without CRI (A, 50.0% and 67.5%; B, 17.9% and 8.3%; H, 14.3% and 18.3%; K, 17.9% and 5.8%, respectively) was statistically different (P = 0.008). Significantly higher K allele frequency was present in primary VUR with CRI children, as it was in the renal survival curve study. A significant increase of LVMI was also found in the A allele group compared with the non-A allele group of KLK1 promoter gene at the age of 18 years old with renal progression. The TGF-beta1 gene polymorphism was determined, and we found significant over-representation of the TT genotype in primary VUR patients with CRI compared with normal renal function (P= 0.0035).. The K allele of KLK1 promoter and TT genotype of TGF-beta1 may be a genetic KLK1 -130 GN and -128 G-C, and the susceptibility factor contributing to progressive renal deterioration in Taiwanese primary VUR children.

Topics: Alleles; Child; Child, Preschool; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Hypertrophy, Left Ventricular; Infant; Kidney Failure, Chronic; Polymorphism, Genetic; Promoter Regions, Genetic; Tissue Kallikreins; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vesico-Ureteral Reflux

Transforming growth factor beta1 (TGF-beta1) affects extracellular matrix (ECM) accumulation. It plays a role in the thickening of the peripheral basement membrane (PBM) and expansion of the mesangium in several renal diseases. The beneficial influence of female gender on the progression of chronic renal diseases may be explained by a favorable effect of estrogen on ECM homeostasis. Interactions between TGF-beta1 and estrogen have been investigated in mesangial cell cultures. However, it is unknown if TGF-beta1-induced glomerulopathy in vivo is influenced by exogenous estrogen. Thus, the aim of the present experiment was to explore whether estrogen prevents the development of TGF-beta1-induced glomerular disease in transgenic mice expressing active TGF-beta1 under control of the Ren-1c promoter. Mice were treated from 3 weeks to 6 weeks of age with 17beta-estradiol release pellets (5-10 microg/kg body weight per day). At the age of 6 weeks, all investigated animals were sacrificed for estimation of PBM thickness, the mesangium per glomerulus [Vv(mes/glom)], the mesangial matrix per glomerulus [Vv(matrix/glom)] and the PBM per glomerulus [Vv(PBM/glom)] using electron microscopy and stereological methods. Furthermore, the total collagen content was determined. We found that TGF-beta1-induced alterations in Vv(mes/glom), Vv(matrix/glom) and Vv(PBM/glom) were prevented in mice exposed to exogenous 17beta-estradiol. In addition, the interstitial fibrosis that develops in TGF-beta1 transgenic mice was attenuated by administration of 17beta-estradiol. In conclusion, estrogen may oppress TGF-beta1-mediated kidney diseases and, thereby, contribute to the protracted development of end-stage renal disease in pre-menopausal women.

Topics: Animals; Basement Membrane; Disease Models, Animal; Estradiol; Extracellular Matrix; Female; Gene Expression; Glomerulonephritis; Hydroxyproline; Kidney; Kidney Failure, Chronic; Kidney Glomerulus; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Promoter Regions, Genetic; Renin; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transgenes

Nephrogenic fibrosing dermopathy (NFD) is a newly recognized cutaneous fibrotic disorder occurring in individuals with end-stage renal disease (ESRD). The aim of the present study was to describe the clinical and histopathologic features of 9 new cases and to characterize the inflammatory cells and expression of transforming growth factor beta1 (TGFbeta1) in affected skin.. Clinical and laboratory assessments, including serology and pulmonary function studies, were performed in 9 patients undergoing long-term dialysis (8 hemodialysis; 1 peritoneal dialysis) for ESRD of diverse etiologies. Skin, fascia, striated muscles, lungs, and heart were examined by histopathology. Inflammatory cells were characterized by immunophenotyping using specific monoclonal antibodies. TGFbeta1 expression was determined by in situ hybridization.. All patients displayed cutaneous features resembling both systemic sclerosis and diffuse fasciitis, with severe loss of motion and flexion contractures in multiple joints. Six patients displayed woody induration of the muscles of the legs, thighs, and forearms. Five of the 6 patients with lung involvement had a reduced diffusion capacity for carbon monoxide on pulmonary function testing. Marked elevations of the erythrocyte sedimentation rate and/or C-reactive protein level were found in 6 patients. Antinuclear antibodies were present at low titers in 4 patients. Histopathologic studies indicated that in addition to the dermis, the fibrotic process affected the subcutaneous tissue, fascia, striated muscles, lungs, and myocardium. Large numbers of CD68+/factor XIIIa+ dendritic cells and increased expression of TGFbeta1 were found in affected skin and muscle.. Our findings indicate that the fibrotic process of NFD affects not only the dermis, but also the subcutaneous tissues, fascia, and other organs, including striated muscles, heart, and lungs. We therefore believe this is a systemic fibrosing process, and we suggest that dialysis-associated systemic fibrosis would be a better term for the condition.

Topics: Adult; Aged; Fascia; Female; Fibrosis; Humans; Immunophenotyping; In Situ Hybridization; Kidney Failure, Chronic; Lung; Male; Middle Aged; Muscles; Myocardium; Renal Dialysis; Skin; Skin Diseases; Transforming Growth Factor beta; Transforming Growth Factor beta1

The aim of this study was to study the incidence of chronic renal dysfunction in patients with more than 5 yr of follow-up following liver transplantation and to evaluate the benefit of decreasing cyclosporine A (CsA) dose combined with mycophenolate mofetil (MMF) on renal function and immune response in these patients. Between 1988 and 1994, 60 children were transplanted, and 86% survived >5 yr post-liver transplantation. Fourteen patients developed chronic renal dysfunction secondary to CsA toxicity as evaluated by renal biopsy. In 11 patients CsA dose was decreased to 40-90 mg/ml target levels and MMF 600 mg/m(2) twice daily was added to the immunosuppressive regimen. Plasma creatinine decreased (from 1.0 +/- 0.03 to 0.8 +/- 0.03 ng/dl, p < 0.007), creatinine clearance increased (from 66.8 +/- 3.0 to 99.2 +/- 6.3 ml/min/1.73 m(2), p < 0.002) and microalbuminuria decreased (from 21.0 +/- 8.6 to 3.6 +/- 1.1 mg/24 h, p < 0.05) after 12 months of CsA combined with MMF therapy. During combined therapy the proliferative, cytolytic response and cytotoxic antibodies showed no significant changes, whereas CD4/CD8 ratio increased (from 1.2 +/- 0.2 to 1.4 +/- 0.1, p < 0.05). Tumor necrosis factor-alpha secretion increased (p < 0.005) during MMF therapy. The release of interleukin-10 was strikingly augmented under both immunosuppressive regimens, but the release of transforming growth factor-beta and interferon-gamma did not change. Our findings indicate that initiation of MMF combined with reduced doses of CsA allowed the recovery of renal function with minor changes in the immune response.

Topics: Adolescent; Child; Cyclosporine; Cytokines; Dose-Response Relationship, Drug; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Interferon-alpha; Interferon-gamma; Interleukin-10; Kidney Failure, Chronic; Kidney Function Tests; Liver Function Tests; Liver Transplantation; Mycophenolic Acid; Time Factors; Transforming Growth Factor beta

To explore curative machanism of Shenle capsule on the 5/6 nephrectomy rats.. Fibrin plate method was applied to examine activity of urinary plasminogen activator(PA). Semi-quantitative analysis was used to observe stained intensity and area of tissue-type plasminogen activator, urokinas-type plasminogen activator/ plasminogen activator inhibitor(tPA, uPA/PAI-1)in remnant renal tissue. Northern blot was employed to analyze the expression of transforming growth factor (TGF-beta) mRNA.. In model control group, the urinary PA activity and protein expression of tPA, uPA were down-regulated, but protein expression of PAI-1, TGF-beta mRNA was up-regulated in remnant renal tissue. In each treated group, the urinary PA activity and protein expression of tPA/uPA were enhanced,but the protein expression of PAI-1, TGF-beta mRNA decreased simultaneously.. Shenle capsule can delay glomerulosclersis and tubulointerstitial fibrotic lesions of remnant kidney by improving the activity of urinary PA and modulating the expression of tPA, uPA/PAI-1 and TGF-beta mRNA.

Topics: Animals; Capsules; Codonopsis; Drug Combinations; Drugs, Chinese Herbal; Female; Kidney; Kidney Failure, Chronic; Leeches; Male; Materia Medica; Nephrectomy; Plasminogen Inactivators; Polyporales; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tissue Plasminogen Activator; Transforming Growth Factor beta; Urokinase-Type Plasminogen Activator

Two genetic loci, PKD I and PKD2, have been identified as being responsible for ADPKD, and PKD1 is known to be associated with a poor prognosis. However, the presence of an intrafamilial study clinical diversity suggests that there are disease-modifying loci. Because the mechanism ofthe renal failure in ADPKD includes a cystic growth and tubulointerstitial atrophy and fibrosis, we studied the associations between 2 polymorphisms in the TGF-beta1 gene, which are known to be associated with chronic tubulointerstitial inflammation, and ADPKD progression in Korean patients.. One hundred and twenty-five individuals who had ADPKD and 47 normal control subjects were genotyped by PCR-RFLP, the T869C (Leu10Pro) variant of TGF-beta gene leader sequence was discriminated with MspA1I and the G915C (Arg25Pro) variants with Bg1I. Statistical significances were determined using the Chi-square test.. The distribution of the alleles for the TGF beta1 Leu10Pro polymorphism in ADPKD was: T 54%, C 46%, which was similar to the Korean (56: 44, p = 0.887) and Western controls (65: 35). In addition, no differences were found between the ESRD and the non-ESRD groups (p = 0.888) or the early hypertension and the normotension groups (p = 0.249). The distribution of alleles for the TGF beta1 Arg25Pro polymorphism showed only the GG type which was different from the Western population controls (G:C = 90:10, p = 0.000).. Our results suggest that the polymorphism at Arg25Pro of TGF-beta1 in the Korean population has an allele distribution different from that ofthe Western population and that the polymorphism at Leu10Pro of TGF-beta1 has no association with the renal progression in Korean ADPKD patients.

Topics: Adult; Aged; Disease Progression; Female; Gene Frequency; Humans; Kidney Failure, Chronic; Korea; Male; Membrane Proteins; Middle Aged; Polycystic Kidney, Autosomal Dominant; Polymorphism, Genetic; Proteins; Transforming Growth Factor beta; Transforming Growth Factor beta1; TRPP Cation Channels

The peritoneal immune compartment is a microenvironment with a particular T-cell repertoire and susceptible to local inflammation. To clarify the role of T lymphocytes in peritoneal immunity, the changes in T-cell subpopulations in peritoneal dialysis effluents (PDEs), and their influence on the response to the treatment of peritonitis and on its prognosis were studied in patients undergoing long-term, continuous ambulatory peritoneal dialysis (CAPD).. A cohort of 36 patients treated with CAPD and who had histories of peritonitis were divided into a group with rapid and a group with delayed response to antibiotics, and were followed for 3 years. CD4/CD8 T-cell ratios, T-cell cytokine mRNA expression patterns and transforming growth factor-beta1 (TGF-beta1) concentrations were examined in PDE during bouts of peritonitis. The change in 4 h D/P creatinine during the peritoneal equilibration test (PET) between year 0 and year 3 was expressed as deltaD/P creatinine.. The serial changes in T-cell subsets in PDE during peritonitis showed two patterns: (i) pattern 1, manifest as a progressive increase in the CD4/CD8 ratio, and associated with a rapid response to treatment; and (ii) pattern 2, manifest as a progressive decrease in the CD4/CD8 ratio, and associated with a delayed response to treatment. The major T-cell phenotypes in PDE during peritonitis were Th1-CD4(+) and Tc2-CD8(+), determined by cloning techniques, RT-PCR and double immunofluorescence staining. TGF-beta1 in the effluent was undetectable in pattern 1 after 7-8 days, but remained detectable at 2 weeks in pattern 2. Pattern 2 patients had a significantly greater decrease (deltaD/P creatinine: -0.198+/-0.086) in solute transport than pattern 1 patients (deltaD/P creatinine: -0.036+/-0.077, P<0.05).. These results suggest that a progressive decrease of the CD4/CD8 ratio in PDE correlates with a persistent expression of TGF-beta1, and plays a pathogenetic role in the evolution of peritonitis, PET deterioration and peritoneal fibrosis. Therefore, patterns of CD4/CD8 T-cell ratio in PDE may predict clinical outcomes of peritonitis in CAPD patients.

Topics: Adult; Biomarkers; CD4 Antigens; CD4-CD8 Ratio; CD8 Antigens; Cytokines; Female; Fluorescent Antibody Technique; Humans; Kidney Failure, Chronic; Male; Microscopy, Fluorescence; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; RNA, Messenger; T-Lymphocyte Subsets; Transforming Growth Factor beta

Chronic renal failure is complicated by high cardiovascular mortality. One key contributor to this mortality is vascular calcification, for which no therapy currently exists. Bone morphogenetic protein 7 is an essential renal morphogen that maintains renal tubular differentiation in the adult and is downregulated in renal failure. Several studies have demonstrated its efficacy in treating various renal diseases in rodents, and it was hypothesized that it would also be an effective treatment of vascular calcification in this setting. Uremia was imposed on LDL receptor null mice (a model of atherosclerosis), which were then treated with bone morphogenetic protein 7 for 15 wk. Uremic animals had increased vascular calcification by histology and chemical analysis. Calcification in treated animals was similar to or less than non-uremic control animals. Cells exhibiting an osteoblast-like phenotype in the vessel wall may be important in the etiology of vascular calcification. Expression of osteocalcin was assessed as a marker of osteoblastic function, and it is shown that it is increased in untreated uremic animals but downregulated to levels similar to non-uremic control animals with treatment. The data are compatible with bone morphogenetic protein 7 deficiency as a pathophysiologic factor in chronic renal failure, and they demonstrate its efficacy as a potential treatment of vascular calcification.

Topics: Animals; Arteriosclerosis; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcinosis; Immunohistochemistry; Kidney Failure, Chronic; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteocalcin; Receptors, LDL; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Vascular Diseases

In hemodialysis patients with an arteriovenous (AV) fistula, access failure is primarily due to fistula stenosis, which predisposes to thrombosis and subsequent access loss. The risk for access failure differs interindividually, an observation that is independent from vascular anatomy in a significant number of patients. Fistula stenosis is histologically characterized by intimal hyperplasia, which is induced by growth factors, among which transforming growth factor beta1 (TGF-beta1) is of major importance. The quantitative production of TGF-beta1 interindividually differs due to polymorphisms in the gene region encoding the signal sequence of the cytokine. We hypothesized that the TGF-beta1 genotype, by influencing the development of arteriovenous fistula stenosis, determines the risk for vascular access failure.. One hundred twenty patients who had undergone placement of an AV fistula for initiation of hemodialysis treatment were genotyped for the polymorphic bases at position +869 and +915 of the TGF-beta1 gene. The primary end-point was time from fistula placement to access failure.. AV fistula patency was significantly associated with the TGF-beta1 genotype (P = 0.0046); patency was 62.4% and 81.2% after 12 months for TGF-beta1 high and intermediate producers, respectively. In contrast, AV fistula patency neither differed between diabetic and nondiabetic patients, nor between patients with and without manifest cardiovascular disease.. Polymorphisms in the gene region encoding the signal sequence of TGF-beta1 influence the risk for hemodialysis access failure. By inducing synthesis of extracellular matrix proteins, overproduction of TGF-beta1 may accelerate the development of intimal hyperplasia, resulting in fistula stenosis and subsequent access failure.

Topics: Aged; Arteriovenous Shunt, Surgical; Diabetic Nephropathies; Female; Genotype; Humans; Kidney Failure, Chronic; Male; Middle Aged; Phenotype; Polymorphism, Genetic; Proportional Hazards Models; Renal Dialysis; Transforming Growth Factor beta; Transforming Growth Factor beta1; Vascular Patency

Tubulointerstitial fibrosis is a hallmark feature of chronic renal injury. Specific therapies to control the progression of renal fibrosis toward end-stage renal failure are limited. Previous studies have demonstrated that expression of endogenous bone morphogenic protein-7 (BMP-7) is reduced in the kidneys of several inducible mouse models of acute and chronic renal disease and that administration of exogenous recombinant human BMP-7 (rhBMP-7) has a beneficial effect on kidney function. Here we report that treatment with rhBMP-7 leads to improved renal function, histology, and survival in mice deficient in the alpha3-chain of type IV collagen and MRL/MpJlpr/lpr lupus mice, two genetic models for chronic renal injury and fibrosis. Such therapeutic benefit is also associated with a significant decrease in the expression of profibrotic molecules, such as type I collagen and fibronectin, in renal fibroblasts. Additionally, rhBMP-7 induces expression of active matrix metalloproteinase-2, which is potentially important for removal of fibrotic matrix. Collectively, these studies provide further evidence for rhBMP-7 as an important bone-associated protein with protective function against renal pathology.

Topics: Animals; Autoantigens; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Cells, Cultured; Collagen Type IV; Disease Models, Animal; Female; Fibroblasts; Fibrosis; Humans; Kidney Failure, Chronic; Lupus Nephritis; Mice; Mice, Inbred MRL lpr; Mice, Mutant Strains; Neuroprotective Agents; Transforming Growth Factor beta

End-stage renal disease (ESRD) is more frequent in African Americans compared to whites. Many factors may be responsible, including genetic differences, increased prevalence of risk factors, and socioeconomic factors; however, to date, these proposed genetic or environmental factors have not provided a satisfactory explanation for the increased risk of ESRD in African Americans. Because renal fibrosis is a correlate of progressive renal failure and a dominant feature of ESRD, and because transforming growth factor beta 1 (TGF-beta1) can induce fibrosis and renal insufficiency, we explored the hypothesis that TGF-beta1 hyperexpression is more frequent in African Americans compared to whites. We tested our hypotheses by measuring TGF-beta1 levels in African Americans and white patients with ESRD, hypertension, and in normal patients. In hypertensive and normal patients, we also evaluated TGF-beta1 mRNA levels, and TGF-beta1 DNA polymorphisms. We demonstrated that circulating levels of TGF-beta1 are higher in African American ESRD patients, hypertensive patients, and normal control patients compared to their white counterparts. We also reported that TGF-beta1 mRNA levels are higher in hypertensives compared to normotensives. Our preliminary genetic analyses suggest that TGF-beta1 DNA polymorphisms may distinguish hypertensives from normotensives, and our laboratory is currently investigating racial differences in TGF-beta1 DNA polymorphisms. Our observations of hyperexpression of TGF-beta1 in African Americans suggest a mechanism for the increased prevalence of renal failure and hypertensive target organ damage in this population.

Topics: Black or African American; Blood Pressure; Female; Humans; Hypertension, Renal; Kidney Failure, Chronic; Linear Models; Male; Middle Aged; Prevalence; Risk Factors; Transforming Growth Factor beta; Transforming Growth Factor beta1; White People

Polymorphisms in the regulatory regions of cytokine genes are associated with high and low cytokine production and may modulate the magnitude of alloimmune responses following transplantation. Ethnicity influences allograft half-life and the incidence of acute and chronic rejection. We have questioned whether ethnic-based differences in renal allograft survival could be due in part to inheritance of cytokine polymorphisms. To address that question, we studied the inheritance patterns for polymorphisms in several cytokine genes (IL-2, IL-6, IL-10, TNF-alpha, TGF-beta, and IFN-gamma) within an ethnically diverse study population comprised of 216 Whites, 58 Blacks, 25 Hispanics, and 31 Asians. Polymorphisms were determined by allele-specific polymerase chain reaction and restriction fragment length analysis. We found striking differences in the distribution of cytokine polymorphisms among ethnic populations. Specifically, significant differences existed between Blacks and both Whites and Asians in the distribution of the polymorphic alleles for IL-2. Blacks, Hispanics and Asians demonstrated marked differences in the inheritance of IL-6 alleles and IL-10 genotypes that result in high expression when compared with Whites. Those of Asian descent exhibited an increase in IFN-gamma genotypes that result in low expression as compared to Whites. In contrast, we did not find significant ethnic-based differences in the inheritance of polymorphic alleles for TNF-alpha. Our results show that the inheritance of certain cytokine gene polymorphisms is strongly associated with ethnicity. These differences may contribute to the apparent influence of ethnicity on allograft outcome.

Topics: Alleles; Cytokines; Ethnicity; Genotype; Humans; Interferon-gamma; Interleukin-10; Kidney Failure, Chronic; Polymorphism, Genetic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Chronic peritoneal dialysis (CPD) is the most commonly used method of pediatric dialysis. The preservation of peritoneal membrane function is essential for successful peritoneal dialysis. Two main factors are responsible for long-term loss of membrane function. Peritonitis, the major complication of CAPD, can be life-threatening and lead to more rapid failure of the technique. The other factor is continuous exposure of peritoneal membrane to bioincompatible dialysis solutions. To investigate the role of repeated peritonitis on peritoneal membrane function, we performed a retrospective study to elucidate the association between peritonitis episodes and peritoneal membrane solute transport characteristics.. From 1996-2000, 32 pediatric peritoneal dialysis patients were included in this study. According to the peritonitis occurrence frequency, 8 patients were divided into HPO group (peritonitis occurrence rate > or = 5 times/year), and 24 patients were divided into LPO group (peritonitis occurrence rate < or = 1 time/year). The mean age of study patients was 13.95 +/- 5.27 years. The peritoneal equilibration test was performed to evaluate the peritoneal membrane dialyzing function.. The mean duration of peritoneal dialysis was 3.31 +/- 1.08 years. The change of peritoneal solute transport (AD/P), computed by subtraction of 4-hour D/P at baseline PET study from that at the last follow-up PET study, showed significant difference (p < 0.05) between HPO (-0.234 + 0.074) and LPO (-0.040 +/- 0.079) groups of children. There was also a significant correlation between repeated peritonitis occurrence and PET deterioration(p < 0.05). The relative risk was 2.63.. Children with frequent peritonitis occurrence have significant decreasing peritoneal solute transport and decreasing PET scaling in follow-up period.

Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Kidney Failure, Chronic; Male; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Peritonitis; Transforming Growth Factor beta; Transforming Growth Factor beta1

Diabetes and renal failure have been associated with extremely high restenosis rates following successful angioplasty, resulting in increased morbidity and mortality. Advanced glycosylation end products (AGEs) accumulate in vascular tissues with aging and at an accelerated rate in diabetes and renal failure. AGEs are particularly abundant at sites of atherosclerotic lesions. AGEs interact with specific receptors (RAGE) present on all cells relevant to the restenosis process including inflammatory cells and smooth muscle cells. AGEs-RAGE interaction in vessel wall may lead to inflammation, smooth muscle cell proliferation, and extracellular matrix production, culminating in exaggerated intimal hyperplasia and restenosis. Following arterial injury, the interaction of AGEs with monocytes expressing RAGE can promote migration of inflammatory cells into the lesion and subsequent release of growth factors and cytokines. Binding of AGEs-RAGE on smooth muscle cells increases chemotactic migration and cellular proliferation. AGEs trigger the generation of reactive oxygen species, and upregulate the multifunctional transcription factor NF-kappa B. Finally, AGEs can augment extracellular matrix production by upregulating transforming growth factor-beta. Thus, accumulation of AGEs in vessel wall provides a common mechanism for the high restenosis rates of patients with diabetes and renal failure.

Topics: Angioplasty, Balloon, Coronary; Coronary Disease; Coronary Restenosis; Cytokines; Diabetic Angiopathies; Diabetic Nephropathies; Extracellular Matrix; Glycation End Products, Advanced; Growth Substances; Humans; Hyperplasia; Kidney Failure, Chronic; Models, Biological; Muscle, Smooth, Vascular; NF-kappa B; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Stents; Transforming Growth Factor beta; Tunica Intima; Tunica Media

It has been previously shown that 2-hydroxyestradiol (2-OHE) attenuates the development of renal disease in genetic nephropathy associated with obesity and the metabolic syndrome. The purpose of this study was to test the hypothesis that 2-OHE, irrespective of its effects on metabolic status and/or obesity, exerts direct renoprotective effects in vivo. First, the effects of increasing doses of 2-OHE on mesangial cell growth, proliferation, and collagen synthesis in isolated rat glomerular mesangial cells were evaluated in vitro. Second, the effects of 12-wk administration of 2-OHE (10 micro g/h per kg) on renal function and structure in chronic puromycin aminonucleoside (PAN)-induced nephropathy in rats were evaluated in vivo. 2-OHE concentration-dependently (0.001 to 1 micro mol/L; P < 0.001) inhibited serum (2.5%)-induced cell growth ((3)H-thymidine incorporation), collagen synthesis ((3)H-proline incorporation), and cell proliferation (cell number). Importantly, the inhibitory effects of 2-OHE (0.1 micro mol/L) were not blocked by ICI182780 (50 micro mol/L), an estrogen receptor antagonist. In vivo, chronic administration of PAN (75 mg/kg + 5 x 20 mg/kg) over 12 wk induced severe chronic renal disease. Chronic treatment with 2-OHE significantly (P < 0.05) attenuated PAN-induced decrease in glomerular filtration, reduced proteinuria, and the elevated BP, and it had no effect on PAN-induced increase in plasma cholesterol and triglycerides levels. 2-OHE had no effects on plasma testosterone levels in male nephropathic animals. Immunohistochemical staining for collagen IV and proliferating cell nuclear antigen (PCNA) in glomeruli and transforming growth factor-beta (TGF-beta) in renal tubular cells were significantly higher in PAN nephropatic rats versus control animals with intact kidneys. PAN also markedly increased glomerular and interstitial macrophage infiltration (ED1(+) cells). 2-OHE had no effects on renal tubular cell TGF-beta, but it significantly reduced glomerular PCNA and collagen IV and glomerular and interstitial macrophage infiltration. In summary, this study provides the first evidence that 2-OHE exerts direct renoprotective effects in vivo. These effects are mediated by estrogen receptor-independent mechanisms and are due, at least in part, to the inhibition of some of the key proliferative mechanisms involved in glomerular remodeling and sclerosis.

Topics: Animals; Blood Pressure; Cell Division; Chronic Disease; Collagen Type IV; Cytoprotection; Estradiol; Glomerular Filtration Rate; Immunohistochemistry; Kidney Failure, Chronic; Kidney Tubules; Male; Proliferating Cell Nuclear Antigen; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; Receptors, Estrogen; Reference Values; Transforming Growth Factor beta

It is thought that transforming growth factor-beta1 (TGF-beta1) might be a key inhibitor of atherogenesis in non-uremic patients. We evaluated the intra- and post-dialytic serum levels of TGF-beta1 in uremic patients to assess if TGF-beta1 is an independent risk factor for cardiovascular diseases, and if any correlation exists between TGF-beta1 and any yet known atherosclerotic risk factors.. We studied 155 patients who were on regular hemodialysis, with or without clinically significant atherosclerotic vascular disease. Forty-one apparently healthy people were enrolled as a control group. TGF-beta1 was evaluated during the midweek dialysis session, at times 0, 30, and 120 minues, at the end of the session, and 3 hours after the session's end. All hitherto known atherosclerotic risk factors also were evaluated. The investigation was performed over a 24-month follow-up.. TGF-beta1 values (mean +/- SD) in dialysis patients were 26.64 +/- 7.0 ng/mL (N=155) compared with 42.31 +/- 6.0 ng/mL in the control group (N=41, P < 0.0001). A weak inverse correlation emerged between TGF-beta1 and age (r=-0.28), TGF-beta1 and lipoprotein(a) [Lp(a); r=-0.35], TGF-beta1 and C-reactive protein (CRP; r=-0.27), and TGF-beta1 and plasminogen activator inhibitor-1 (PAI-1; r=-0.41). TGF-beta1 also correlated with albumin (r=0.31). In the coronary heart disease (CHD) group (N=32) the TGF-beta1 was 26.2 +/- 4.9 ng/mL; in the cerebrovascular disease (CVD) group (N=8) it was 26.7 +/- 3.7 ng/mL and in the peripheral vascular disease (PVD) group (N=9) it was 25.4 +/- 1.7 ng/mL. In dialysis patients with no cardiovascular disease (N=80) TGF-beta1 was 35.1 +/- 6.8 ng/mL (P < 0.0001 vs. CHD, CVD and PVD patients). TGF-beta1 was significantly lower among those patients with triple coronary vessel disease than with the other CHD patients. The Cox analysis demonstrated that a 1 ng/mL reduction in TGF-beta1 concentration was associated with a 9% increase in the relative risk of a cardiovascular event.. TGF-beta1 was significantly reduced in hemodialysis patients, in particular in those with severe cardiovascular disease. Baseline TGF-beta1, diabetes mellitus and serum albumin levels proved to be the only independent contributors to atherosclerotic risk in dialysis patients.

Topics: Adult; Aged; Aged, 80 and over; Coronary Artery Disease; Female; Follow-Up Studies; Genotype; Humans; Kidney Failure, Chronic; Logistic Models; Male; Middle Aged; Myocardial Ischemia; Predictive Value of Tests; Renal Dialysis; Risk Factors; Survival Analysis; Transforming Growth Factor beta; Transforming Growth Factor beta1; Uremia

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

During progression of chronic renal disease, qualitative and quantitative changes in the composition of tubular basement membranes (TBMs) and interstitial matrix occur. Transforming growth factor (TGF)-beta(1)-mediated activation of tubular epithelial cells (TECs) is speculated to be a key contributor to the progression of tubulointerstitial fibrosis. To further understand the pathogenesis associated with renal fibrosis, we developed an in vitro Boyden chamber system using renal basement membranes that partially mimics in vivo conditions of TECs during health and disease. Direct stimulation of TECs with TGF-beta(1)/epithelial growth factor results in an increased migratory capacity across bovine TBM preparations. This is associated with increased matrix metalloproteinase (MMP) production, namely MMP-2 and MMP-9. Indirect chemotactic stimulation by TGF-beta(1)/EGF or collagen type I was insufficient in inducing migration of untreated TECs across bovine TBM preparation, suggesting that basement membrane integrity and composition play an important role in protecting TECs from interstitial fibrotic stimuli. Additionally, neutralization of MMPs by COL-3 inhibitor dramatically decreases the capacity of TGF-beta(1)-stimulated TECs to migrate through bovine TBM preparation. Collectively, these results demonstrate that basement membrane structure, integrity, and composition play an important role in determining interstitial influences on TECs and subsequent impact on potential aberrant cell-matrix interactions.

Topics: Adult; Animals; Basement Membrane; Cattle; Cell Movement; Cells, Cultured; Chemotaxis; Electrophoresis, Polyacrylamide Gel; Epidermal Growth Factor; Epithelial Cells; Extracellular Matrix; Fibrosis; Humans; Kidney Failure, Chronic; Kidney Tubules; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Rabbits; Transforming Growth Factor beta; Transforming Growth Factor beta1

Potential determinants of chronic renal disease (CRD) progression were studied in male Munich-Wistar rats subjected to 5/6 nephrectomy and treated with candesartan (Csn; n = 30) or enalapril (Ena; n = 27) from 5 wk postsurgery. Despite control of systolic blood pressure (SBP; 24 wk: Csn = 143 +/- 9; Ena = 148 +/- 8 mmHg), urinary protein excretion rates (U(pr)V) increased over 24 wk (Csn = 92 +/- 10; Ena = 99 +/- 8mg/day). Glomerulosclerosis scores (GS) at 24 wk were similar for Csn (42 +/- 7%) vs. Ena (42 +/- 4%), values close to those of untreated controls at 12 wk (43 +/- 4%). At 24 wk, SBP and UprV correlated strongly with GS, together accounting for 72% of the variance in GS. Renal cortex mRNA levels (determined by competitive RT-PCR) for transforming growth factor (TGF)-beta1 and monocyte chemoattractant protein (MCP)-1 were elevated in Csn and Ena at 12 wk and remained higher at 24 wk vs. sham. Strong correlations were evident among TGF-beta1, MCP-1, and interleukin-1beta and renal injury at 24 wk. Cns and Ena are thus equally effective renoprotective agents in this model. During renin-angiotensin system inhibition, renoprotection is dependent on control of both SBP and UprV. Incomplete suppression of renal cytokine gene expression may also contribute to CRD progression.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chemokine CCL2; Enalapril; Endothelin-1; Interleukin-1; Kidney Cortex; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Transforming Growth Factor beta1

Although immunosuppressive regimens are effective, rejection occurs in up to 50% of patients after orthotopic liver transplantation (OLT), and there is concern about side effects from long-term therapy. Knowledge of clinical and immunogenetic variables may allow tailoring of immunosuppressive therapy to patients according to their potential risks. We studied the association between transforming growth factor-beta, interleukin-10, and tumor necrosis factor alpha (TNF-alpha) gene polymorphisms and graft rejection and renal impairment in 121 white liver transplant recipients. Clinical variables were collected retrospectively, and creatinine clearance was estimated using the formula of Cockcroft and Gault. Biallelic polymorphisms were detected using polymerase chain reaction-based methods. Thirty-seven of 121 patients (30.6%) developed at least 1 episode of rejection. Multivariate analysis showed that Child-Pugh score (P =.001), immune-mediated liver disease (P =.018), normal pre-OLT creatinine clearance (P =.037), and fewer HLA class 1 mismatches (P =.038) were independently associated with rejection. Renal impairment occurred in 80% of patients and was moderate or severe in 39%. Clinical variables independently associated with renal impairment were female sex (P =.001), pre-OLT renal dysfunction (P =.0001), and a diagnosis of viral hepatitis (P =.0008). There was a significant difference in the frequency of TNF-alpha-308 alleles among the primary liver diseases. After adjustment for potential confounders and a Bonferroni correction, the association between the TNF-alpha-308 polymorphism and graft rejection approached significance (P =.06). Recipient cytokine genotypes do not have a major independent role in graft rejection or renal impairment after OLT. Additional studies of immunogenetic factors require analysis of large numbers of patients with appropriate phenotypic information to avoid population stratification, which may lead to inappropriate conclusions.

Topics: Adult; Cytokines; Female; Graft Rejection; Humans; Interleukin-10; Kidney Failure, Chronic; Liver Transplantation; Male; Middle Aged; Multivariate Analysis; Polymorphism, Genetic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The pathological role of oxidative stress in patients treated by hemodialysis has gained increasing recognition in recent years. Because complications related to vascular access are a major source of morbidity, immunohistochemical evidence of oxidative stress and activation of growth factors were examined in native arteriovenous (AV) fistulae (n = 11) and expanded polytetrafluoroethylene (ePTFE) grafts (n = 15) recovered from hemodialysis patients at the time of surgical revision or resection. To show the presence of oxidative stress in tissues, three markers were chosen: N(epsilon)(carboxymethyl)lysine, a structurally identified advanced glycation end product; 4-hydroxy-2,3-nonenol, a lipid peroxidation product; and redox-active transition metals bound to proteins, a source of Fenton chemistry-generated free radicals. Markers of cell growth and proliferation were endothelin-1 (ET-1), a potent mitogenic peptide implicated in the formation of intimal hyperplasia; transforming growth factor-beta (TGF-beta), a stimulus to vascular cell growth and matrix production; and platelet-derived growth factor (PDGF), a mediator of intimal hyperplasia. All specimens studied showed significant intimal hyperplasia. In general, the neointima close to the vascular lumen of the AV fistula and the pseudointima close to the lumen of the ePTFE graft were positive for oxidative stress markers. At sites of injury, especially in the presence of histological evidence of inflammation and healing, expression of oxidative markers was particularly intense. Prominent staining of PDGF was shown at sites of anastomotic hyperplasia and in neovasculature. TGF-beta was associated with proliferation or repair in both AV fistulae and ePTFE grafts. ET-1 staining was most intense in the neointima and pseudointima. This study showed histochemical colocalization of markers of oxidative stress with growth factors known to contribute to intimal hyperplasia.

Topics: Adult; Aged; Arteriovenous Anastomosis; Arteriovenous Fistula; Arteriovenous Shunt, Surgical; Biomarkers; Constriction, Pathologic; Endothelin-1; Female; Growth Substances; Humans; Hyperplasia; Iron; Kidney Failure, Chronic; Lipid Peroxidation; Lysine; Male; Middle Aged; Oxidation-Reduction; Oxidative Stress; Platelet-Derived Growth Factor; Polytetrafluoroethylene; Renal Dialysis; Transforming Growth Factor beta; Tunica Intima; Vascular Patency

The progression of chronic renal diseases is considered as an irreversible process that eventually leads to end-stage renal failure characterized by extensive tissue fibrosis. At present, chronic renal fibrosis is incurable and the incidence of affected patients is on the rise worldwide. In this study, we demonstrate that delivery of hepatocyte growth factor (HGF) gene via systemic administration of naked plasmid vector markedly ameliorated renal fibrosis in an animal model of chronic renal disease induced by unilateral ureteral obstruction. A high level of exogenous HGF protein was detected in the obstructed kidneys following intravenous injection of naked plasmid encoding human HGF. Delivery of human HGF gene induced a sustained activation of extracellular signal-regulated kinases-1 and -2 in the obstructed kidneys. Exogenous HGF expression dramatically inhibited alpha-smooth muscle actin expression, attenuated renal interstitial accumulation and deposition of collagen I and fibronectin. In addition, exogenous HGF suppressed renal expression of pro-fibrogenic cytokine TGF-beta1 and its type I receptor in vivo. These results suggest that systemic administration of naked plasmid vector introduces a high level of exogenous HGF to the diseased kidneys, and that HGF gene transfer may provide a novel therapeutic strategy for amelioration of chronic renal fibrosis in vivo.

Topics: Actins; Animals; Blotting, Western; Chronic Disease; Collagen; DNA; Enzyme-Linked Immunosorbent Assay; Fibronectins; Fibrosis; Gene Expression; Genetic Therapy; Hepatocyte Growth Factor; Kidney Failure, Chronic; Male; Mice; Mice, Inbred Strains; Mitogen-Activated Protein Kinases; Models, Animal; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta

Advanced glycation end product-modified beta2-microglobulin (AGE-beta2m) is an important component of dialysis-related amyloidosis (DRA). Its presence induces monocyte chemotaxis and the release of the proinflammatory cytokines through macrophage activation. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that also has chemotactic activity for monocytes at very low (0.1 to 10 pg/mL) concentrations and inhibits proinflammatory cytokine production of macrophages. In this study, we investigated the role of TGF-beta in the pathogenesis of DRA.. We performed an immunohistochemical study of DRA tissues (8 cases) to confirm the existence of TGF-betas and their receptors; we also performed a chemotaxis assay of human monocytes as well as enzyme-linked immunosorbent assay (ELISA) of TGF-beta1, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-1 receptor antagonist (IL-1Ra) in the supernatant of human monocyte-derived macrophage cell culture under varying conditions of incubation with TGF-beta1, AGE-beta2m, and TGF-beta1 antibody additions.. There was positive staining for TGF-betas (types 1, 2, and 3) and their receptors (types I, II, and III) in infiltrated macrophages (CD68+), synovial lining cell, as well as vascular walls around amyloid deposition. AGE-beta2m also induced TGF-beta1 production by macrophages in a dose-dependent manner (410 +/- 80 pg/mL at 12.5 microg/mL, 621 +/- 62 pg/mL at 25 microg/mL, and 776 +/- 62 pg/mL at 50 microg/mL of AGE-beta2m). AGE-beta2m induced significant TNF-alpha and IL-1Ra production by macrophage. The addition of exogenous TGF-beta1 (0.1 to 10 ng/mL) decreased AGE-beta2m-induced TNF-alpha production and increased IL-1Ra production in a dose-dependent fashion. IL-1beta production was not effected by any experimental conditions. In chemotaxis assay, anti-TGF-beta1 antibody (0.1 to 10 microg/mL) attenuated AGE-beta2m-induced monocyte chemotaxis.. These results provide the first evidence to our knowledge for the presence of TGF-beta in DRA tissue, as well as the stimulatory action of AGE-beta2m on tissue macrophages. In turn, TGF-beta suppresses the proinflammatory activation of macrophages, suggesting a dual role for TGF-beta in the inflammatory process of DRA. These observations may provide a pathophysiologic link between TGF-beta and DRA.

Topics: Aged; Amyloidosis; beta 2-Microglobulin; Cells, Cultured; Chemotaxis; Chronic Disease; Female; Glycation End Products, Advanced; Humans; Interleukin 1 Receptor Antagonist Protein; Kidney Failure, Chronic; Macrophages; Male; Middle Aged; Monocytes; Receptors, Transforming Growth Factor beta; Renal Dialysis; Sialoglycoproteins; Synovial Membrane; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

The issue of whether recombinant human erythropoietin (rhEPO) increases thrombosis of arteriovenous (AV) fistulae used for hemodialysis remains unclear. Thrombosis often occurs at stenotic segments of fistulae where there is marked intimal hyperplasia and extracellular matrix accumulation. Increased expression of transforming growth factor-beta1 (TGF-beta1) has been shown to be involved in the development of atherosclerotic lesions by promoting intimal hyperplasia and extracellular matrix accumulation. To clarify the role of rhEPO in the development of stenosis of AV fistulae, this study examined expression of the erythropoietin receptor (EPO-R), TGF-beta1, plasminogen activator inhibitor type 1 (PAI-1), cellular fibronectin containing an extra domain A (EDA+), and TGF-beta1 mRNA, and assessed in situ rhEPO binding in tissue specimens from seven cutaneous veins and eight patent and seven stenosed portions of AV fistulae of patients undergoing dialysis. Prominent intimal hyperplasia was evident in the stenosed segments. Significant elevation in expression of EPO-R and TGF-beta1 was noted in patent AV fistulae compared to the cutaneous veins. Significant enhancement of EPO-R and TGF-beta expression was detected in the stenotic fistulae. Fibronectin EDA+ and PAI-1 expression was increased in intimal hyperplasia compared to patent fistulae and cutaneous veins. Elevated EPO-R expression was further confirmed by in situ binding of biotin-labeled rhEPO in stenosed tissue specimens. It is hypothesized that increased rhEPO binding due to elevated EPO-R expression contributes to the development of AV fistula stenosis caused by intimal hyperplasia and extracellular matrix accumulation in response to increased TGF-beta1 expression in patients receiving hemodialysis.

Topics: Adult; Aged; Analysis of Variance; Arteriovenous Shunt, Surgical; Constriction, Pathologic; Female; Fibronectins; Humans; Immunoenzyme Techniques; In Situ Hybridization; Kidney Failure, Chronic; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Receptors, Erythropoietin; Renal Dialysis; RNA, Messenger; Transforming Growth Factor beta

Topics: Disease Progression; Extracellular Matrix; Humans; Kidney; Kidney Failure, Chronic; Prognosis; Transforming Growth Factor beta

We previously reported elevated levels of TGF-beta1 in patients with renal carcinoma. Certain aspects led us to ask whether they might be caused by chronic damage to the kidney(s). Here we report on an extended set of patients with various renal diseases, lung cancer, humoral immunodeficiency and controls. For latent TGF-beta1 in plasma, we find that the control, immunodeficiency, lung cancer and kidney transplant groups do not differ significantly (means, 7.0-8.8 ng/ml). Also, acute short-term renal stress (extracorporal lithotrypsy) does not lead to an increase of TGF-beta1. However, the pyelonephritis patients present with levels of 19.0 ng/ml, chronic extracorporal dialysis patients with 15.5 ng/ml, and renal cell carcinoma patients with 22.8 ng/ml. For active TGF-beta1 these findings are exactly recovered. For serum levels, only the renal carcinoma group presents with significantly elevated levels of TGF-beta1. Kidney transplantation seems to normalize TGF-beta1 levels, while in the kidney cancer patients surgery has an effect only in part of the group. We conclude that elevated plasma TGF-beta1 levels are common in at least two chronic renal disease conditions, and that it normalizes with restoration of renal function. It is tempting to speculate that chronic elevation of TGF-beta1 in these patients may be critically involved in these conditions predisposing to renal cancer.

Topics: Carcinoma, Renal Cell; Common Variable Immunodeficiency; Humans; Kidney Diseases; Kidney Failure, Chronic; Kidney Neoplasms; Kidney Transplantation; Lithotripsy; Lung Neoplasms; Pyelonephritis; Transforming Growth Factor beta

The present study examined the long-term consequences of warm renal ischemia (WRI) with or without renal ablation. Male Sprague-Dawley rats (250-300 g) were subjected to 60 min of complete WRI by pedicle clamping and then followed for 52 wk. Animals were organized into four groups: rats in which both kidneys were subjected to warm ischemia (2WIK); rats with left WRI and right nephrectomy (1WIK); uninephrectomized rats with a left nonischemic kidney (1NK); and sham-operated rats (2NK). Additional animals were studied at 24 h, 7 days, and 16 and 32 wk. In the first week after WRI, rats from the 2WIK and 1WIK groups displayed a similar degree of acute renal damage. After recovering from acute renal failure, 1WIK rats developed progressive and severe proteinuria, whereas it was mild in the 2WIK group, as well as in the 1NK and 2NK groups. Only animals from the 1WIK group developed severe chronic renal failure, glomerulosclerosis, interstitial fibrosis, and upregulation of transforming growth factor-beta(1) (TGF-beta(1)) gene, which was associated with increased TGF-beta(1) protein expression in tubular epithelial cells, arterioles, and in areas of mononuclear interstitial cell infiltrate. On the contrary, long-term renal TGF-beta(1) expression, function, and histology were similar in 2WIK and 2NK rats. The present study shows that prolonged bilateral WRI, when both kidneys are retained in place, induces very mild long-term renal lesions as opposed to the severe renal scarring observed when WRI is combined with contralateral nephrectomy.

Topics: Acute Kidney Injury; Animals; Body Temperature; Chronic Disease; Ischemia; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Nephrons; Organ Size; Rats; Rats, Sprague-Dawley; Recovery of Function; Renal Circulation; RNA, Messenger; Transforming Growth Factor beta

Topics: Adult; Biomarkers; Creatinine; Diabetes Mellitus; Diabetic Nephropathies; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Reference Values; Transforming Growth Factor beta

Although the renoprotective effect of calcium-channel blockers (CCBs) has been examined in several models of hypertensive nephropathy, it remains unclear. It also remains to be clarified whether CCBs prevent the progression to end-stage renal failure in chronic progressive glomerulonephritis (GN). A new rat model of progressive mesangioproliferative GN was used to study the effect of benidipine hydrochloride, a long-acting dihydropyridine CCB, on the clinical features and morphological lesions.. This animal model of progressive GN was induced by a single intravenous injection of anti-Thy-1 monoclonal antibody (MoAb 1-22-3) two weeks after unilateral nephrectomy. After 10 weeks of treatment with benidipine (1, 3, and 5 mg/kg body weight, p.o.) or hydralazine (5 mg/kg body weight, p.o.), systolic blood pressure (SBP), urinary protein excretion, creatinine clearance, glomerulosclerosis index, tubulointerstitial lesion index, glomerular cross-sectional area, and glomerular expression of transforming growth factor-beta (TGF-beta) and alpha-smooth muscle actin (alpha-SMA) were measured.. Untreated rats developed hypertension, massive proteinuria, renal dysfunction, severe glomerular and tubulointerstitial injury, higher glomerular size, and marked glomerular staining for TGF-beta and alpha-SMA, while uninephrectomized control rats did not. Each dose of benidipine and hydralazine equally reduced SBP to uninephrectomized control levels. Three and five mg/kg/day of benidipine increased creatinine clearance, ameliorated glomerular and tubulointerstitial injury, and reduced glomerular staining for TGF-beta and alpha-SMA, but 1 mg/kg/day of benidipine and hydralazine failed. Only a dose of 5 mg/kg/day of benidipine reduced glomerular size, although it did not reduce the size to control levels.. These results indicate that in a rat model of progressive mesangioproliferative GN, benidipine prevents the progression to end-stage renal failure in a dose-dependent manner. This renoprotective action is associated with the suppression of glomerular expression of TGF-beta and alpha-SMA.

Topics: Actins; Animals; Blood Pressure; Body Weight; Calcium Channel Blockers; Creatinine; Dihydropyridines; Disease Models, Animal; Disease Progression; Fluorescent Antibody Technique; Glomerulonephritis, Membranoproliferative; Hydralazine; Kidney Failure, Chronic; Kidney Glomerulus; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Transforming Growth Factor beta; Vasodilator Agents

The mechanisms underlying progressive renal fibrosis are unknown, but the common association of fibrosis and microvascular loss suggests that hypoxia per se may be a fibrogenic stimulus.. To determine whether human renal fibroblasts (HRFs), the primary matrix-producing cells in the tubulointerstitium, possess oxygen-sensitive responses relevant to fibrogenesis, cells were exposed to 1% O2 in vitro.. Hypoxia simultaneously stimulated extracellular matrix synthesis and suppressed turnover with increased production of collagen alpha1(I) (Coll-I), decreased expression of collagenase, and increased tissue inhibitor of metalloproteinase (TIMP)-1. These effects are time dependent, require new RNA and protein synthesis, and are specific to hypoxia. The changes in Coll-I and TIMP-1 gene expression involve a heme-protein O2 sensor and protein kinase- and tyrosine kinase-mediated signaling. Although hypoxia induced transforming growth factor-beta1 (TGF-beta1), neutralizing anti-TGF-beta1-antibody did not block hypoxia-induced Coll-I and TIMP-1 mRNA expression. Furthermore, hypoxic-cell conditioned-medium had no effect on the expression of these mRNAs in naive fibroblasts, suggesting direct effects on gene transcription. Transient transfections identified a hypoxia response element (HRE) in the TIMP-1 promoter and demonstrated HIF-1-dependent promoter activation by decreased ambient pO2.. These data suggest that hypoxia co-ordinately up-regulates matrix production and decreases turnover in renal fibroblasts. The results support a role for hypoxia in the pathogenesis of fibrosis and provide evidence for novel, direct hypoxic effects on the expression of genes involved in fibrogenesis.

Topics: Actins; Antimutagenic Agents; Cell Division; Cell Hypoxia; Cell Size; Cell Survival; Cells, Cultured; Chelating Agents; Cobalt; Collagen; Collagenases; Culture Media, Conditioned; Deferoxamine; Extracellular Matrix; Fibroblasts; Gene Expression Regulation, Enzymologic; Humans; Hypoxia; Kidney Cortex; Kidney Failure, Chronic; Oxygen; Promoter Regions, Genetic; Protein Kinase C; Protein-Tyrosine Kinases; RNA, Messenger; Tissue Inhibitor of Metalloproteinase-1; Transcription, Genetic; Transfection; Transforming Growth Factor beta; Transforming Growth Factor beta1

Transforming growth factor-beta1 (TGF-beta1) may play a major role in the pathogenesis of glomerulopathy and end-stage renal disease (ESRD). The aim of this study was to explore the functional consequences of localized overproduction of TGF-beta1 in relation to glomerular ultrastructure and the composition of the extracellular matrix (ECM) in the inner medulla. We used a transgenic mouse with overexpression of TGF-beta1 targeted to the juxtaglomerular apparatus (JGA) by the Ren-1c promoter. The kidney function was evaluated using urine production and metabolite excretion over a 24-hour period, glomerular filtration rate (GFR), and concentrating ability. The glomerular structure was analyzed in terms of volume, ie, the volume of the mesangium per glomerulus (Vv[mes/glom]) and the volume of the matrix per glomerulus (Vv[matrix/glom]), ECM per glomerulus, the area of the filtration surface, and the thickness of the peripheral basement membrane (PBM). Immunohistochemistry or in situ hybridization was used to examine the expression of aquaporin 2 (AQP2), plasminogen activator inhibitor-1 (PAI-1), and the composition of the ECM in the inner medulla. The mice exhibited polyuria, reduced concentrating ability, decreased GFR, and albuminuria paralleled by increased glomerular volume, with increased volume of ECM, decreased filtration surface, and thickening of the PBM being detectable between 1 and 2 months of age. The deposition of glomerular ECM was accompanied by increased levels of PAI-1. As estimated by excretion of Clara cell protein-1 (CC16) and lysozyme, tubular damage occurred only in older mice. Collagen Type I was deposited in the inner medulla in the presence of normal AQP2-expression in the collecting ducts. This study reached the following conclusions: (a) TGF-beta1 reduces the GFR and the glomerular filtration surface, (b) TGF-beta1 induces albuminuria in association with widening of the PBM, (c) expansion of the mesangial volume seems to precede the widening of the PBM, (d) TGF-beta1-induced accumulation of glomerular ECM is partly explained by increased PAI-1 expression, (e) Decreased concentrating ability and polyuria caused by accumulation of ECM in the inner medulla may be an early marker of glomerular diseases associated with increased expression of TGF-beta1 in man.

Topics: Aldosterone; Animals; Aquaporin 2; Aquaporin 6; Aquaporins; Circadian Rhythm; Disease Models, Animal; Diuresis; Female; Glomerular Filtration Rate; Humans; Juxtaglomerular Apparatus; Kidney Failure, Chronic; Kidney Glomerulus; Male; Mice; Mice, Transgenic; Promoter Regions, Genetic; Reference Values; Swine; 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

Obstructive nephropathy is a primary cause of renal insufficiency in infants and children. This study was designed to distinguish the reversible and irreversible cellular consequences of temporary unilateral ureteral obstruction (UUO) on the developing kidney.. Rats were subjected to UUO or sham operation in the first 48 hours of life, and the obstruction was removed five days later (or was left in place). Kidneys were removed for study 14 or 28 days later. In additional groups, kidneys were removed at the end of five days of obstruction. Immunoreactive distribution of renin was determined in arterioles, and the distribution of epidermal growth factor, transforming growth factor-beta1, clusterin, vimentin, and alpha-smooth muscle actin was determined in tubules and/or interstitium. The number of glomeruli, glomerular maturation, tubular atrophy, and interstitial collagen deposition was determined by morphometry. Renal cellular proliferation and apoptosis were measured by proliferating cell nuclear antigen and the TdT uridine-nick-end-label technique, respectively. The glomerular filtration rate was measured by inulin clearance.. Renal microvascular renin maintained a fetal distribution with persistent UUO; this was partially reversed by the relief of obstruction. Although glomerular maturation was also delayed and glomerular volume was reduced by UUO, the relief of obstruction prevented the reduction in glomerular volume. Although relief of obstruction did not reverse a 40% reduction in the number of nephrons, the glomerular filtration rate of the postobstructed kidney was normal. The relief of obstruction did not improve tubular cell proliferation and only partially reduced apoptosis induced by UUO. This was associated with a persistent reduction in the tubular epidermal growth factor. In addition, the relief of obstruction reduced but did not normalize tubular expression of transforming growth factor-beta1, clusterin, and vimentin, all of which are evidence of persistent tubular injury. The relief of obstruction significantly reduced interstitial fibrosis and expression of alpha-smooth muscle actin by interstitial fibroblasts, but not to normal levels.. The relief of obstruction in the neonatal rat attenuates, but does not reverse, renal vascular, glomerular, tubular, and interstitial injury resulting from five days of UUO. Hyperfiltration by remaining nephrons and residual tubulointerstitial injury in the postobstructed kidney are likely to lead to deterioration of renal function later in life.

Topics: Actins; Animals; Animals, Newborn; Child; Clusterin; Disease Models, Animal; Epidermal Growth Factor; Glomerular Filtration Rate; Glycoproteins; Humans; Infant; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Tubules; Molecular Chaperones; Rats; Rats, Sprague-Dawley; Renin; Time Factors; Transforming Growth Factor beta; Ureteral Obstruction; Vimentin

The renin-angiotensin system is thought to be involved in the progression of glomerulonephritis (GN) into end-stage renal failure (ESRF) because of the observed renoprotective effects of angiotensin-converting enzyme inhibitors (ACEIs). However, ACEIs have pharmacological effects other than ACE inhibition that may help lower blood pressure and preserve glomerular structure. We previously reported a new animal model of progressive glomerulosclerosis induced by a single intravenous injection of an anti-Thy-1 monoclonal antibody, MoAb 1-22-3, in uninephrectomized rats. Using this new model of progressive GN, we examined the hypothesis that ACEIs prevent the progression to ESRF by modulating the effects of angiotensin II (Ang II) on the production of transforming growth factor-beta (TGF-beta) and extracellular matrix components.. We studied the effect of an ACEI (cilazapril) and an Ang II type 1 receptor antagonist (candesartan) on the clinical features and morphological lesions in the rat model previously reported. After 10 weeks of treatment with equihypotensive doses of cilazapril, cilazapril plus Hoe 140 (a bradykinin receptor B2 antagonist), candesartan, and hydralazine, we examined systolic blood pressure, urinary protein excretion, creatinine clearance, the glomerulosclerosis index, and the tubulointerstitial lesion index. We performed a semiquantitative evaluation of glomerular immunostaining for TGF-beta and collagen types I and III by immunofluorescence study and of these cortical mRNA levels by Northern blot analysis.. Untreated rats developed massive proteinuria, renal dysfunction, and severe glomerular and tubulointerstitial injury, whereas uninephrectomized control rats did not. There was a significant increase in the levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I and III in untreated rats. Cilazapril and candesartan prevented massive proteinuria, increased creatinine clearance, and ameliorated glomerular and tubulointerstitial injury. These drugs also reduced levels of glomerular protein and cortical mRNA for TGF-beta and collagen types I and III. Hoe 140 failed to blunt the renoprotective effect of cilazapril. Hydralazine did not exhibit a renoprotective effect.. These results indicate that ACEIs prevent the progression to ESRF by modulating the effects of Ang II via Ang II type 1 receptor on the production of TGF-beta and collagen types I and III, as well as on intrarenal hemodynamics, but not by either increasing bradykinin activity or reducing blood pressure in this rat model of mesangial proliferative GN.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Bradykinin; Bradykinin Receptor Antagonists; Cilazapril; Collagen; Disease Models, Animal; Glomerulonephritis, Membranoproliferative; Hydralazine; Kidney Failure, Chronic; Male; Proteinuria; Rats; Rats, Wistar; Renal Circulation; Renin-Angiotensin System; Tetrazoles; Transforming Growth Factor beta

The morphologic alterations in the kidney and the retina that can be present in patients with diabetic microangiopathy are mediated by growth factors. Vascular endothelial growth factor (VEGF) is a mediator of neoangiogenesis in diabetic retinopathy. Transforming growth factor-beta (TGF-beta) is involved in the extracellular matrix proliferation in diabetic nephropathy. The aim of the present study was to investigate the presence of VEGF and TGF-beta1 in peritoneal effluents of patients undergoing continuous ambulatory peritoneal dialysis who are being treated with glucose-containing dialysis solutions in relation to parameters of peritoneal transport. Standard peritoneal permeability analyses with 3.86% glucose dialysate were performed in 16 stable patients undergoing peritoneal dialysis (PD) (median duration of PD 39 months, range 1 to 104 months). The power relationship that is present between dialysate/serum (D/S) ratios of serum proteins that are transported only across the peritoneal membrane and their molecular weights was used to predict the D/S ratios when diffusion would be the only explanation for the measured dialysate concentration. It was assumed that all TGF-beta1 in the circulation was bound to alpha2-macroglobulin. The D/S ratios of VEGF (P < .0005) and TGF-beta1 (P < .015) were significantly higher than expected when VEGF and TGF-beta1 would have been transported from the circulation only by diffusion. No relationship was present between the effluent concentration attributed to the local production of VEGF (LVEGF) and that of TGF-beta1 (LTGF-beta1). LVEGF correlated with the mass transfer area coefficient (MTAC) creatinine value (r = 0.69, P < .007), MTAC urate value (r = 0.60, P < .02), and glucose absorption value (r = 0.75, P < .004), all reflections of the peritoneal vascular surface area. A negative correlation was observed between the transcapillary ultrafiltration (926 mL/4 h, 394 to 1262 mL/4 h) and LVEGF (r = -0.52, P < .045). This negative tendency was also observed between the net ultrafiltration (622 mL/4 h, -43 to 938 mL/4 h) and LVEGF (r = -0.48) but did not reach significance. LVEGF and the duration of treatment did not correlate, possibly because of the relatively small number of patients. LTGF-beta1 showed no relationship with transport parameters or duration of treatment. In conclusion, we found evidence for the local production of both VEGF and TGF-beta1 in the peritoneal membrane of patients undergoing long-term perit

Topics: Biological Transport; Capillaries; Creatinine; Cross-Sectional Studies; Dialysis Solutions; Endothelial Growth Factors; Female; Glucose; Humans; Kidney Failure, Chronic; Lymphokines; Male; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Regression Analysis; Transforming Growth Factor beta; Ultrafiltration; Urea; Uric Acid; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Recent reports have suggested the involvement of interleukin-4 (IL-4) in glomerular pathophysiology. Using immunohistochemistry and reverse transcriptase polymerase chain reaction we investigated the renal lesions in transgenic (tg) mice with widely distributed IL-4 expression including the kidney, and measured the serum levels of the cytokines transforming growth factor-beta (TGF-beta) and IL-4 by ELISA. Transgenic animals exhibited glomerular hypertrophy with progressive mesangial sclerosis leading to renal failure. Renal IL-4 transcript expression, mesangial accumulation of collagen types I, III, IV and V, and immune deposition accompanied by increased expression of TGF-beta1 protein and mRNA were observed. Seven day-old transgenic animals showed early renal fibrotic changes in the absence of immune deposits or TGF-beta1 upregulation. The sera of transgenic mice not only showed elevated levels of circulating IL-4 (tg: 76.6 pg/ml +/- 7.1 vs wildtype (wt): < 3 pg/ml), but significantly decreased TGF-beta1 levels (tg: 18.9 ng/ml +/- 4.1 vs wt: 38.7 ng/ml +/- 2.9; P < 0.005). The disease severity correlated with the serum IL-4/TGF-beta1 ratio rather than with the IL-4 concentration. These data suggest that renal IL-4 production results in matrix accumulation prior to any immunological insult, that increased circulating IL-4/TGF-beta1 ratios are associated with renal immunopathological manifestations and that upregulation of renal TGF-beta1 expression following glomerular Ig deposition accelerates the sclerosis and exacerbates disease development.

Topics: Animals; Disease Progression; Glomerulonephritis; Immunoenzyme Techniques; Interleukin-4; Kidney Failure, Chronic; Mice; Mice, Transgenic; Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Transforming Growth Factor beta; Up-Regulation

Inhibition of the renin-angiotensin system by both angiotensin II type 1 receptor antagonists (AT1As) and angiotensin I-converting enzyme inhibitors (ACEIs) shows renoprotective effects in rats with chronic renal failure when treatment is started in the early phase of renal injury. In this study, we examined the renal protective effects of candesartan cilexetil (TCV-116), an AT1A, and enalapril, an ACEI, in the progressive phase of renal injury in 5/6 nephrectomized rats.. Candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) were orally administered once a day for 4 weeks (the short-term experiment) or 16 weeks (the long-term experiment) to 5/6 nephrectomized rats beginning 15 weeks after the nephrectomy, that is, after they had already showed marked proteinuria.. In vehicle-treated rats, proteinuria, glomerulosclerosis, and interstitial fibrosis developed. Moreover, enhanced expression of transforming growth factor-beta1 (TGF-beta1) in the injured glomeruli was observed. These adverse changes progressed with time, and in the short-term experiment, both drugs inhibited them. In the long-term experiment, the progressive proteinuria and the elevation of blood pressure were similarly attenuated by both drugs. However, candesartan cilexetil significantly inhibited the progression of glomerulosclerosis, the expression of TGF-beta1, and interstitial fibrosis, whereas enalapril did not.. These results indicate that candesartan cilexetil shows potent and long-term preventive effects against the progression of previously developed renal injury.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Blood Urea Nitrogen; Creatinine; Dinoprostone; Disease Models, Animal; Enalapril; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Tetrazoles; Transforming Growth Factor beta

Transforming growth factor-beta1 (TGF-beta1) is an immunoregulatory and fibrogenic cytokine. In an earlier in vitro study, we demonstrated that cyclosporine (CsA) increases TGF-beta1 transcription rate in human T lymphocytes. Herein, we explored whether CsA augments the in vivo expression of TGF-beta1 in humans.. The inherent difficulty in studying the in vivo effect of CsA in humans was circumvented by investigating stable end-stage renal disease patients who were preconditioned with CsA before their living donor renal transplantation. Sera and peripheral blood mononuclear cells were obtained from CsA-preconditioned patients and quantified for TGF-beta1 expression at the mRNA (by competitive polymerase chain reaction) and protein (sandwich enzyme-linked immunosorbent assay) levels.. Our studies demonstrated a significant increase in TGF-beta1 expression after CsA therapy. The stimulatory effect was unique to TGF-beta1, and CsA did not increase interleukin (IL)-10, IL-6, IL-2, or tumor necrosis factor-alpha expression.. Our first-time demonstration of a TGF-beta1-selective in vivo stimulatory effect of CsA in humans: (1) advances a TGF-beta1-centered hypothesis for the beneficial (immunosuppression) and detrimental (fibrosis, hypertension) effects of CsA use, and (2) broadens the mechanism of immunosuppressive action of CsA to include heightened expression of an endogenous immunosuppressive cytokine.

Topics: Cyclosporine; Humans; Immunosuppressive Agents; Interleukin-10; Interleukin-2; Interleukin-6; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Polymerase Chain Reaction; T-Lymphocytes; Transcription, Genetic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

End-stage renal disease (ESRD) is more frequent in African Americans (blacks) compared to Caucasian Americans (whites). Identification of remediable causes of the increased prevalence has the potential to reduce the excess burden of ESRD. Because renal fibrosis is a correlate of progressive renal failure and a dominant feature of ESRD, and because transforming growth factor-beta 1 (TGF-beta 1) can induce fibrosis and renal insufficiency, we explored the hypothesis that TGF-beta 1 hyperexpression is more frequent in black ESRD patients compared to white ESRD patients. Our postulate was tested by determining circulating levels of TGF-beta 1 protein in the sera of 56 black and 42 white ESRD patients treated by chronic hemodialysis. A solid-phase sandwich enzyme-linked immunosorbent assay, specific for TGF-beta 1, was used to quantify TGF-beta 1 levels in the ESRD cohort. Additional cytokines implicated in tissue repair/remodeling, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), were also measured. Our investigation demonstrated a significantly higher concentration of TGF-beta 1 protein but not that of IL-6 or TNF-alpha in blacks compared to whites. Our observation that TGF-beta 1 is hyperexpressed in black ESRD patients suggests a mechanism for the increased prevalence of renal failure (since TGF-beta 1 hyperexpression can result in renal insufficiency in experimental models) among the black population.

Topics: Black People; Cohort Studies; Female; Gene Expression; Humans; Hypertension, Renal; Interleukin-6; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Prognosis; Risk Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; White People

We evaluated the intraplatelet and plasma levels of transforming growth factor beta (TGF-beta) in patients with or without renal osteodystrophy (ROD) who were undergoing hemodialysis (HD). Intraplatelet and plasma levels of TGF-beta were examined before and after HD, and compared with those from healthy controls. Patients undergoing HD had significantly higher mean intraplatelet levels of TGF-beta before and after HD than did the healthy subjects (22.7 +/- 7.8 and 29.5 +/- 15.8 vs. 18.7 +/- 7.9 ng/10(5) platelets; p < .05). The mean intraplatelet and plasma levels of TGF-beta in patients after HD were significantly increased than those before HD and in healthy subjects (p < .05). Moreover, patients with ROD showed a significantly higher mean intraplatelet and plasma levels of TGF-beta than that without ROD (p < .05). To investigate the effects of TGF-beta on ROD in HD patients, we evaluated such parameters as parathyroid hormone (PTH) and alkaline phosphatase (ALP), which reflect the lesions of ROD. The mean intraplatelet level of TGF-beta was not correlated with either para-meter. Meanwhile, no correlation was observed between the intraplatelet level of TGF-beta and the hematocrit (Hct). Similarly, no correlation was observed between the intraplatelet levels of TGF-beta and the dose of erythropoietin (EPO) administered. These findings indicate that metabolism of TGF-beta occurs during HD and overproduction of TGF-beta may play an important role in the pathogenesis of ROD.

Topics: Blood Platelets; Case-Control Studies; Chronic Kidney Disease-Mineral and Bone Disorder; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Transforming Growth Factor beta

Chronic renal disease (CRD) is generally thought to be incurable, except through renal transplantation, and the number of patients with CRD is on the increase. Glomerulosclerosis and tubulointerstitial fibrosis represent the morphological equivalent of end-stage CRD. In this study, we demonstrated the preventive effect of hepatocyte growth factor (HGF) on the progression of renal dysfunction and fibrosis, using a spontaneous mouse model for CRD (ICGN strain). The mice progressively developed glomerular sclerotic injury, tubular atrophy, and renal dysfunction until they were 17 wk of age. When recombinant HGF was injected into these mice during a 4-wk-period (from weeks 14-17 after birth), DNA synthesis of tubular epithelial cells was found to be 4.4-fold higher than in mice without HGF injection, thereby suggesting tubular parenchymal expansion promoted by HGF. Notably, HGF suppressed the expression of transforming growth factor-beta and of platelet-derived growth factor as well as myofibroblast formation in the affected kidney. Consequently, the onset of tubulointerstitial fibrosis was almost completely inhibited by HGF, while HGF attenuated the progression of glomerulosclerosis, both leading to preventing manifestation of renal dysfunction. From our results, supplement therapy with HGF may be taken into consideration as a novel option for prevention and treatment of CRD.

Topics: Animals; Disease Models, Animal; Fibrosis; Glomerulonephritis; Hepatocyte Growth Factor; Kidney; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Tubules; Mice; Nephrosis; Platelet-Derived Growth Factor; Recombinant Proteins; Transforming Growth Factor beta

Evidence suggests that transforming growth factor beta 1 (TGF-beta 1), a multifunctional cytokine, induces renal extracellular matrix production and glomerular hypertrophy. The aim of the present study was to investigate the effect of captopril on the expression of TGF-beta 1 mRNA in a rat model of chronic renal failure: five-sixths nephrectomy. Chronic renal disease was induced by removal of the right kidney and ligation of three blood vessels supplying the left kidney. Sham-operated animals were used as controls. RNA was extracted from the viable remnant kidney of rats 1 day and 1 and 2 weeks following five-sixths nephrectomy and from the kidneys of rats who underwent sham surgery. TGF-beta 1 mRNA was induced within 24 h of partial nephrectomy, similar to that reported for early-onset genes. Subsequently, TGF-beta 1 mRNA expression continued to increase over the next 2-4 weeks. The upregulation of TGF-beta 1 correlated with the degree of proteinuria. Both the increase in TGF-beta 1 mRNA and proteinuria were abrogated by captopril treatment. In addition, no change in expression of ALK-5 or type II TGF-beta receptors following five-sixths nephrectomy was observed. These data suggest that captopril may protect against development of glomerulosclerosis and proteinuria by reducing TGF-beta 1 expression and hence matrix production.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Northern; Captopril; Disease Models, Animal; Gene Expression; Kidney; Kidney Cortex; Kidney Failure, Chronic; Nephrectomy; Peptidyl-Dipeptidase A; Proteinuria; Rats; Receptors, Transforming Growth Factor beta; RNA, Messenger; Transforming Growth Factor beta

The renal protective properties of candesartan cilexetil (TCV-116), an angiotensin II type 1 receptor antagonist (AT1A), and enalapril, an angiotensin I converting enzyme inhibitor (ACEI), were investigated in 5/6 nephrectomized (NX) rats. Candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) were administered orally to 5/6 NX rats for four weeks (during the early phase of disease development) or 16 weeks (through the late phase). In vehicle-treated rats, proteinuria, glomerulosclerosis, interstitial mononuclear cell (MNC) infiltration and interstitial fibrosis developed. Moreover, immunohistological studies showed enhanced expression of transforming growth factor-beta 1 (TGF-beta 1) in the injured glomeruli. Both drugs inhibited these adverse changes in the early phase. In the late phase, the progressive proteinuria, interstitial MNC infiltration were attenuated by both drugs. However, candesartan cilexetil significantly inhibited the progression of glomerulosclerosis, the expression of TGF-beta 1 and the interstitial fibrosis, while enalapril did not. Candesartan cilexetil and enalapril showed comparable hypotensive effects after the 16-week administration. These results indicate that candesartan cilexetil shows a more potent protective effect than enalapril against the progression of renal injury in the late phase. Thus, an AT1A might be more useful than an ACEI for the treatment of patients with chronic renal failure.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Disease Progression; Enalapril; Fibrosis; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; Tetrazoles; Transforming Growth Factor beta

We recently demonstrated that the administration of indoxyl sulfate (dietary protein metabolite) to 5/6-nephrectomized rats accelerated the progression of chronic renal failure by increasing the transforming growth factor (TGF)-beta 1 synthesis in the kidneys, which enhanced the renal expressions of tissue inhibitor of metalloproteinase (TIMP)-1 and type 1 collagen, leading to renal fibrosis. The aim of the present study was to clarify the mechanism by which the administration of indoxyl sulfate increases TGF-beta 1 in the kidneys of uremic rats. Since infiltrative monocytes are suggested to be an important source of TGF-beta 1 in tubulointerstitial fibrosis, we examined the effect of indoxyl sulfate administration to uremic rats on the renal gene expression of intercellular adhesion molecule (ICAM)-1, which is involved in the infiltration of monocytes to kidneys. Indoxyl sulfate administration was observed to enhance the mRNA levels of ICAM-1 as well as those of TGF-beta 1, TIMP-1 and pro alpha 1 (I) collagen in the renal cortex of 5/6-nephrectomized uremic rats. In addition, we demonstrated in vitro that the addition of indoxyl sulfate significantly increased the synthesis of TGF-beta 1 in cultured proximal tubular cells. Thus, the overload of indoxyl sulfate in uremic kidneys increased the infiltration of monocytes and directly increased the synthesis of TGF-beta 1 in proximal tubular cells.

Topics: Animals; Cells, Cultured; Disease Progression; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Indican; Intercellular Adhesion Molecule-1; Kidney; Kidney Failure, Chronic; Rats; RNA, Messenger; Swine; Transforming Growth Factor beta

We and others have already reported that Onpi-to (TJ-8117), a Kampo medicine composed mainly of Rhei Rhizoma, has a beneficial effect on an adenine-induced renal failure model and 5/6 nephrectomized renal failure. However, little is known about the detailed mechanism of this medicine when used for renal failure. The present study was designed to clarify whether or not TJ-8117 affects TGF-beta 1 production or activation in glomeruli of 5/6 nephrectomized rats. TJ-8117 (400 mg/kg/ day) and captopril (50 mg/kg/day) were administered as drinking water from the day immediately after the operation and continued throughout the experiment. All rats were sacrificed at 4 weeks and renal cortical tissue was removed to quantify the protein and activity of TGF-beta 1 and activities of metalloproteinase. TIMP expression and extracellular matrix (collagen type I, IV) in the glomeruli were analysed histologically. TJ-8117 inhibited proteinuria, and the accumulation of collagen type I and IV in glomeruli of nephrectomized rats. In addition, TJ-8117 inhibited the TGF-beta 1 positive area in the glomeruli and the elevation of mature TGF-beta 1 level in the renal cortex of nephrectomized rats. In the TJ-8117 treated group, activities of metalloproteinase 1, 2 or 9 in the renal cortex were elevated compared with the control group. Captopril failed to affect the TGF-beta 1 level. We also found that the constitutive herbs in TJ-8117, Rhei Rhizoma and Ginseng radix, inhibited the process from inactive TGF-beta 1 to mature TGF-beta 1.

Topics: Animals; Disease Models, Animal; Drugs, Chinese Herbal; Kidney Failure, Chronic; Male; Nephrectomy; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

1. Blood transfusion confers immune suppression with improved allograft survival. The aim of this study was to evaluate the effect of blood transfusion on the production of T-helper-2 cytokines and transforming growth factor beta, which are associated with suppression of allograft rejection. An additional aim was to try to identify which blood cell type is mostly responsible for the blood transfusion effect. Production of interleukin-4, interleukin-10 and transforming growth factor beta by peripheral blood mononuclear cells isolated from patients with end-stage renal disease was measured in vitro. These assays were performed before, and 4h, 4, 7 and 14 days after a single blood transfusion and the transfusion of one unit of leucocyte-free erythrocytes. 2. Blood transfusion stimulated a significant rise in the production of all three cytokines measured. Transfusion of erythrocytes had no effect on the production of interleukin-4 or interleukin-10. 3. It is suggested that blood transfusion enhances the production of interleukin-4, interleukin-10 and transforming growth factor beta. These cytokines may inhibit production of T-helper 1 and pro-inflammatory cytokines, deactivate cytotoxic cells and thereby suppress allograft rejection. It is further suggested that the leucocyte is the transfused cell type which is mostly associated with induction of this immunosuppressive response.

Topics: Adult; Aged; Blood Transfusion; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Erythrocyte Transfusion; Female; Humans; Interleukin-10; Interleukin-4; Interleukins; Kidney Failure, Chronic; Leukocytes; Male; Middle Aged; Transforming Growth Factor beta