tretinoin and Hypertension

Immune abnormalities and inflammatory responses play critical roles in progression of hypertension. Basic studies have confirmed that Th17 cell and related cytokines are important in promoting hypertension-mediated organ damage, but few clinical evidences have been published. Therefore, our study aimed to investigate the relationship between Th17 cell and its related cytokines and hypertension-mediated organ damage in human.. This study enrolled 179 patients with hypertension (including 92 with hypertension-mediated organ damage and 87 without hypertension-mediated organ damage) and 63 healthy participants. The proportion of Th17 cells in peripheral blood mononuclear cells was measured by flow cytometry. The concentrations of interleukin-17 and interleukin-23 were detected by enzyme-linked immunosorbent assay. Real time-polymerase chain reaction was used to detect the mRNA expression levels of interleukin-17, retinoic acid-related orphan receptor (ROR) γt and signal transducer and activator of transcription-3 (STAT-3).. The proportion of Th17 cells, the concentration of interleukin-17 and interleukin-23 and the mRNA expression levels of interleukin-17, retinoic acid-related orphan receptor γt and signal transducer and activator of transcription-3 were significantly increased in hypertension-mediated organ damage group compared with those in non-hypertension-mediated organ damage group and control group (P < 0.005).. Th17 cells and their associated cytokines may be involved in hypertension-mediated organ damage formation and may be able to serve as new biomarkers of hypertension-mediated organ damage and potential therapeutic targets.

Topics: Case-Control Studies; Cytokines; Humans; Hypertension; Interleukin-17; Interleukin-23; Leukocytes, Mononuclear; RNA, Messenger; T-Lymphocytes, Regulatory; Th17 Cells; Tretinoin

Hypertension is a multifactorial disease with limited knowledge of the involved mechanisms. p,p'-DDE ( p,p'-dichlorodiphenyldichloroethylene) is a pollutant commonly found in tissues that interferes with endocrine signaling. This study aimed to evaluate the mechanism of hypertension triggered by p,p'-DDE exposure in the presence or absence of a HF (high-fat) diet in rats. The renin-angiotensin system (RAS) was evaluated by qPCR in liver and adipose tissue (AT), and a transcriptome analysis comparing visceral AT of HF diet and HF/DDE groups was performed. HF diet influenced RAS, but the p,p'-DDE effect was more evident in liver than in AT (interaction between the diet and p,p'-DDE treatment affected aldosterone receptor and angiotensin converting enzyme 2 expression in liver, p < 0.05, two-way ANOVA). p,p'-DDE induced a decrease in the expression of genes involved in the retinoid acid biosynthesis pathway (Crabp1; -2.07-fold; p = 0.018), eNOS activation (Nos1; -1.64-fold; p = 0.012), and regulation and urea cycle (Ass1; -2.07-fold; p = 0.02). This study suggested that p,p'-DDE may play a fundamental role in the pathogenesis of hypertension, not exclusively in RAS but also by induction of hyperuricemia and increased oxidative stress, which may lead to endoplasmic reticulum stress and vascular injury.

Topics: Angiotensin-Converting Enzyme 2; Animals; Dichlorodiphenyl Dichloroethylene; Environmental Pollutants; Humans; Hypertension; Liver; Male; Peptidyl-Dipeptidase A; Rats; Rats, Wistar; Receptors, Mineralocorticoid; Tretinoin

Therapeutic administration of retinoids is often accompanied with undesirable side effects, including an increase in lipid levels in up to 45% of treated patients. We tested the hypothesis of whether spontaneously hypertensive rat (SHR) and congenic SHR.PD-(D8Rat42-D8Arb23)/Cub (SHR-Lx) strains, differing only in a 14-gene region of chromosome 8 and previously shown to display differential sensitivity to the teratogenic effects of retinoic acid, could serve as a pharmacogenetic model set of the metabolic side effects of retinoid therapy.. Male, 15-week old rats (n = 12/strain) of SHR and SHR-Lx strains were fed a high-sucrose diet for 2 weeks and subsequently treated either with all-trans retinoic acid (15 mg/kg) or only with a vehicle for 16 days (n = 6/strain/treatment), while still on the high-sucrose diet. We assessed the morphometric and metabolic profiles of all groups, including glucose tolerance tests, levels of insulin, adiponectin, free fatty acids, concentrations of triglycerides and cholesterol in 20 lipoprotein fractions under conditions of both high-sucrose diet and high-sucrose diet plus all-trans retinoic acid administration.. SHR-Lx displayed substantially greater sensitivity to a number of all-trans retinoic acid-induced metabolic dysregulations compared with SHR, resulting in impairment of glucose tolerance, increased visceral adiposity, and substantially greater increase of circulating triglyceride concentrations, accompanied by a shift towards their less favorable distribution into the lipoprotein fractions. These observations closely mimic the common side effects of retinoid therapy in humans, rendering SHR-Lx an experimental pharmacogenetic model of atRA-induced dyslipidemia.

Topics: Animals; Animals, Congenic; Disease Models, Animal; Dyslipidemias; Glucose Tolerance Test; Hypertension; Insulin Resistance; Lipid Metabolism; Male; Pharmacogenetics; Rats; Rats, Inbred SHR; Sucrose; Tretinoin

Vitamin A (retinol) and its analogs (retinoids) are important regulators of cell proliferation, differentiation, immune function, and apoptosis. The kidneys are target organs for vitamin A action. Retinoic acid (RA), a vitamin A metabolite, is involved in embryonic kidney patterning through the control of receptor tyrosine kinase expression, which modulates ureteric bud branching morphogenesis. Vitamin A status of the mother profoundly affects kidney organogenesis of the newborn. In rodents, mild vitamin A deficiency results in a 20% reduction of nephron number. In adult humans, nephron number varies between 0.3 and 1.3 million per kidney, which is accepted as normal. However, recent studies indicate that humans at the low end of nephron number are predisposed to primary hypertension. Because RA regulates nephron mass, its optimal availability during nephrogenesis is critical. RA levels in the embryo are affected by several factors, such as maternal vitamin A nutrition and disturbances in retinol metabolism. Maternal vitamin A deficiency during pregnancy is widespread in developing countries and segments of these populations may be exposed to low vitamin A during fetal life when nephron number is determined. Infants are likely to be born with suboptimal nephrons and may develop primary hypertension later in life. Although maternal vitamin A deficiency is not common in developed countries, congenital nephron number nevertheless varies widely, indicating low fetal RA levels due to common variants of the enzymes that convert retinol to RA. These infants might require heightened surveillance for hypertension later in life.

Topics: Animals; Female; Fetus; Gene Expression Regulation, Developmental; Humans; Hypertension; Infant, Newborn; Maternal-Fetal Exchange; Nephrons; Pregnancy; Pregnancy Complications; Tretinoin; Vitamin A; Vitamin A Deficiency

Studies show general agreement that all-trans retinoic acid (atRA) has been linked to the regulation of G protein-coupled receptor (GPCRs) signaling. To further validate effects of atRA on the cardiovascular GPCRs, the present study was designed to assess whether atRA will modulate orphan receptor APJ, a homologue of angiotensin II type 1 (AT(1)) receptor.. Real-time polymerase chain reaction and Western blot methods were performed to examine the expression of APJ and its endogenous ligand apelin in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats after chronic atRA treatment.. APJ and apelin expression were markedly depressed in placebo-treated SHR, compared with WKY rats (p<0.01). However, in atRA-treated SHR, a significant upregulation of APJ and apelin expression was observed in both heart and aorta (p<0.05), accompanied by a reduction of AT(1) expression, an elevation of serum nitric oxide levels and a subsequent decrease of blood pressure.. Chronic atRA treatment activates gene and protein expression of APJ and apelin and reduces blood pressure in SHR, suggesting that atRA may regulate the balance between apelin-APJ and angiotensin II-AT(1) signaling and have potential clinical value in the prevention and treatment of human hypertension.

Topics: Animals; Apelin; Apelin Receptors; Blood Pressure; Blotting, Western; Carrier Proteins; Gene Expression Regulation; Hypertension; Intercellular Signaling Peptides and Proteins; Male; Nitric Oxide; Polymerase Chain Reaction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled; RNA, Messenger; Signal Transduction; Tretinoin

There are in vitro data linking all-trans retinoic acid (atRA) with inhibition of hypertrophy and hyperplasia in cardiomyocytes, vascular smooth muscle cells, and fibroblasts. In the present study, we tested the hypothesis that chronic treatment with atRA may blunt the process of myocardial remodeling in spontaneously hypertensive rats (SHR). Four-week-old male SHR were treated with atRA (5 or 10 mg.kg-1.day-1) given daily for 3 mo by gavage; age- and sex-matched Wistar-Kyoto rats (WKY) and placebo-treated SHR served as controls. At the end of the treatment period, cardiac geometry and function were assessed by Doppler echocardiography. Histological examination and RIA were performed to evaluate medial thickening of intramyocardial and renal arteries, perivascular and interstitial collagen content, and atrial natriuretic peptide (ANP) and IGF-I in the heart, respectively. The novel finding of the present study is that atRA prevented hypertrophy of intramyocardial and intrarenal arteries and ventricular fibrosis. However, atRA treatment did not lower blood pressure or left ventricular weight and left ventricular weight-to-body weight ratio in SHR. atRA did not change cardiac geometry and function as assessed by Doppler echocardiography. atRA showed no influence on either ANP or IGF-I levels. In conclusion, the present study suggests that chronic atRA treatment prevents medial thickening of intramyocardial and intrarenal arteries and ventricular fibrosis during the development of hypertension. Left ventricular hypertrophy and cardiac geometry and function are not changed by atRA treatment.

Topics: Animals; Body Weight; Coronary Vessels; Drug Administration Schedule; Fibrosis; Heart; Heart Ventricles; Hemodynamics; Hypertension; Hypertrophy; Male; Myocardium; Organ Size; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Artery; Tretinoin; Tunica Media

Topics: Acute Kidney Injury; Antineoplastic Agents; Dexamethasone; Humans; Hypertension; Incidence; Leukemia, Promyelocytic, Acute; Leukocyte Count; Leukocytosis; Leukostasis; Mortality; Premedication; Respiratory Distress Syndrome; Risk Factors; Syndrome; Tretinoin