Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity is one of the most frequently encountered medical problems of our time. Among the complications of this pathologic entity, renal disease is an important issue and its pathophysiologic mechanisms are a challenge for the physician, since a variety of etiologic factors are implicated in its genesis. For example, hypertension, hyperlipidemia and insulin resistance affect renal function, each one in a different way. Obesity seems to be a state in which kidneys demonstrate morphological and functional alterations, while hormonal and growth factors play a significant role. Among them, leptin, a recently discovered cytokine, has undergone extended investigation and has proven to be a factor that contributes to renal disease, mainly through mechanisms that involve activation of the TGF-beta system resulting in glomerulopathy and related clinical symptoms. Experiments in animals have revealed interesting aspects as far as the role of leptin in kidney function. Understanding the underlying mechanisms of obesity-related glomerulopathy may become a valuable aid in handling an obese patient with renal disease and associated problems.
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PMID:Obesity and renal disease: a possible role of leptin. 1661 10

Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction mediated by excess placenta-derived soluble VEGF receptor 1 (sVEGFR1 or sFlt1) is emerging as a prominent component in disease pathogenesis. We report a novel placenta-derived soluble TGF-beta coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery. sEng inhibits formation of capillary tubes in vitro and induces vascular permeability and hypertension in vivo. Its effects in pregnant rats are amplified by coadministration of sFlt1, leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth. sEng impairs binding of TGF-beta1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-beta signaling in the vasculature. Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia.
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PMID:Soluble endoglin contributes to the pathogenesis of preeclampsia. 1675 67

Recent studies have suggested a role for aldosterone in the pathogenesis of renal injury. This study investigated the potential contributions of Rho-kinase and TGF-beta pathways to aldosterone-induced renal injury. Rats were uninephrectomized and then treated for 5 wk with 1% NaCl in a drinking solution and one of the following: Vehicle (2% ethanol, subcutaneously; n = 9); aldosterone (0.75 microg/h, subcutaneously; n = 9); or aldosterone + fasudil, a specific Rho-kinase inhibitor (10 mg/kg per d, subcutaneously; n = 8). Phosphorylation of myosin phosphate target subunit-1 (MYPT1) and Smad2/3 in renal cortical tissue was measured by Western blotting with anti-phospho MYPT1 and Smad2/3 antibodies, respectively. Rats that received aldosterone infusion exhibited hypertension and severe renal injury characterized by proteinuria, glomerular sclerosis, and tubulointerstitial fibrosis with increases in alpha-smooth muscle actin staining and numbers of monocytes/macrophages in the interstitium. Renal cortical mRNA levels of types I and III collagen, TGF-beta, connective tissue growth factor, and monocyte chemoattractant protein-1 as well as Smad2/3 phosphorylation were significantly increased in rats that received aldosterone infusion. All of these changes were associated with an increase in renal tissue MYPT1 phosphorylation. Treatment with fasudil did not alter BP but significantly ameliorated proteinuria and renal injury in rats that received aldosterone infusion. Furthermore, fasudil prevented MYPT1 phosphorylation and markedly decreased alpha-smooth muscle actin staining, numbers of monocytes/macrophages, mRNA levels of types I and III collagen, TGF-beta, connective tissue growth factor and monocyte chemoattractant protein-1, and Smad2/3 activity in renal cortical tissues. These results provide evidence, for the first time, that Rho-kinase is substantially involved in aldosterone-induced renal injury through activation of a TGF-beta-dependent pathway.
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PMID:Involvements of Rho-kinase and TGF-beta pathways in aldosterone-induced renal injury. 1679 May 7

Chronic angiotensin (ANG) II infusions into rats lead to augmented intrarenal levels of ANG II and inflammatory factors, impaired renal function, and progressive hypertension. Residual effects persist after cessation of ANG II infusions, as manifested by a hypertensive response to high-salt intake. This study was performed to determine the residual cytokines and chemokines following the cessation of ANG II infusion. Male Sprague-Dawley rats, maintained on a normal diet, received either a sham operation or continuous ANG II infusion (120 ng/min) subcutaneously via minipumps. The ANG II-infused rats were further subdivided into three subgroups. Minipumps were removed on day 12 with subsequent harvesting of kidneys at 0, 3, and 6 days after cessation of ANG II infusion. After 12 days of ANG II infusion, systolic blood pressure, interstitial fibrosis, preglomerular hypertrophy, and interstitial macrophage infiltration were significantly enhanced compared with the shams. By 3 days following the cessation of ANG II infusion, systolic blood pressure was normalized; however, interstitial fibrosis and preglomerular hypertrophy were still present. Furthermore, increased interstitial macrophage infiltration was still present 6 days after cessation of ANG II infusion. Importantly, augmented mRNA levels of monocyte chemotactic protein (MCP)-1 (1.55 +/- 0.15 vs. 1.00 +/- 0.13, relative ratio) and transforming growth factor (TGF)-beta(1) (1.52 +/- 0.16 vs. 1.00 +/- 0.08) persisted 6 days after the withdrawal of ANG II infusion (1.60 +/- 0.20 for MCP-1 and 1.43 +/- 0.17 for TGF-beta(1)). Thus, the ANG II-induced activation of MCP-1 and TGF-beta(1) is sustained and may account for the persistent effect of chronic ANG II infusions on interstitial macrophage infiltration, suggesting a possible mechanism for the development of salt sensitivity in ANG II-dependent hypertension.
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PMID:Sustained renal interstitial macrophage infiltration following chronic angiotensin II infusions. 1680 6

We investigated the effects of maternal glucocorticoid exposure in the spiny mouse, a precocial species with a relatively long gestation, few offspring, and in which nephrogenesis is complete before birth. We hypothesized that exposure of the fetus to glucocorticoids before the formation of glomeruli would result in adult hypertensive offspring with fewer nephrons. Furthermore, we hypothesized that this nephron deficit would result from changes in expression of genes involved in branching morphogenesis. Osmotic pumps implanted in pregnant spiny mice at midgestation (day 20) delivered dexamethasone (dex; 125 microg/kg) or saline for 60 h. Females were killed at day 23 of gestation and kidneys were frozen for real-time PCR analysis or allowed to deliver their offspring. At 20 wk of age, blood pressure was measured in the offspring for 1 wk before nephron number was determined using unbiased stereology. Males and females exposed to dex had significantly fewer nephrons (male: saline: 7,870 +/- 27, dex: 6,878 +/- 173; female: saline: 7,526 +/- 62, dex: 5,886 +/- 382; P < 0.001) compared with controls. Dex had no effect on basal blood pressure. Fetal kidneys collected at day 23 of gestation from dex-exposed mothers showed increased mRNA expression of BMP4 (P < 0.05), TGF-beta(1) (P < 0.05), genes known to inhibit branching morphogenesis and gremlin (P < 0.01), an antagonist of BMP4, compared with saline controls. This study shows for the first time an upregulation of branching morphogenic genes in the fetal kidney in a model of excess maternal glucocorticoids that leads to a nephron deficit in the adult. This study also provides evidence that a reduced nephron number does not necessarily lead to development of hypertension.
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PMID:Maternal dexamethasone treatment at midgestation reduces nephron number and alters renal gene expression in the fetal spiny mouse. 1694 81

Transforming growth factor (TGF-beta) is a multifunctional peptide growth factor that has an important role in the regulation of cell growth, differentiation, and repair in a variety of tissues. In mammals, the cytokine has three isoforms, TGF-beta1, TGF-beta2, and TGF-beta3. TGF- beta1 is up-regulated by Ang II and induction of TGF-beta1 causes cardiac fibrosis. The stimulus that triggers the expression of TGF-beta1 may be repeated causing continual injury, which is associated with an increase in the activity of Ang II in heart tissue. The interplay between Ang II and TGF-beta1 causes continued activation that may result in chronic hypertension and progressive myocardial fibrosis, leading to heart failure. The regulation of TGF-beta1 secretion and action involves complex transcriptional events. Overproduction of TGF-beta1 underlies tissue fibrosis. Understanding the actions and signaling transduction of TGF-beta could lead to the development of therapeutic options that may be effective in inhibiting myocardial fibrosis triggered by TGF-beta1 in heart failure.
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PMID:Role of transforming growth factor-beta in the progression of heart failure. 1701 66

Inhibition of the renin-angiotensin-aldosterone system (RAAS) is one of the most powerful maneuvers to slow progression of renal disease. Angiotensin II (AngII) has emerged in the past decade as a multifunctional cytokine that exhibits many nonhemodynamic properties, such as acting as a growth factor and profibrogenic cytokine, and even having proinflammatory properties. Many of these deleterious functions are mediated by other factors, such as TGF-beta and chemoattractants that are induced in the kidney by AngII. Moreover, understanding of the RAAS has become much more complex in recent years with the identification of novel peptides (e.g., AngIV) that could bind to specific receptors, elucidating deleterious effects, and non-angiotensin-converting enzyme (ACE)-mediated generation of AngII. The ability of renal cells to produce AngII in a concentration that is much higher than what is found in the systemic circulation and the observation that aldosterone may be engaged directly in profibrogenic processes independent of hypertension have added to the complexity of the RAAS. Even renin has now been identified to have a "life on its own" and mediates profibrotic effects via binding to specific receptors. Finally, drugs that are used to block the RAAS, such as ACE inhibitors or certain AngII type 1 receptor antagonists, may have properties on cells independent of AngII (ACE inhibitor-mediated outside-inside signaling and peroxisome proliferator-activated receptor-gamma stimulatory effects of certain sartanes). Although blockade of the RAAS with ACE inhibitors, AngII type 1 receptor antagonists, or the combination of both should be part of every strategy to slow progression of renal disease, a better understanding of the novel aspects of the RAAS should contribute to the development of innovative strategies not only to completely halt progression but also to induce regression of human renal disease.
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PMID:Renin-angiotensin-aldosterone system and progression of renal disease. 1703 13

Genetic studies in familial pulmonary arterial hypertension (FPAH) have revealed heterozygous germline mutations in the bone morphogenetic protein type II receptor (BMPR-II), a receptor for the transforming growth factor (TGF)-beta/bone morphogenetic protein (BMP) superfamily. PAH is characterized by intense remodeling of small pulmonary arteries by myofibroblast and smooth muscle proliferation. BMPR-II mutation in pulmonary artery smooth muscle cells contributes to abnormal growth responses to BMPs and TGF-beta. Reduced expression or function of BMPR-II signaling leads to exaggerated TGF-beta signaling and altered cellular responses to TGF-beta. The likely mechanism involves an interaction between BMP and TGF-beta-regulated Smad pathways. In endothelial cells, BMPR-II mutation increases the susceptibility of cells to apoptosis. The combination of increased endothelial apoptosis and failure of growth suppression in pulmonary artery smooth muscle cells provides important clues to the cellular pathogenesis of PAH. The reciprocal regulation of TGF-beta and BMP signaling in models of tissue repair may provide new approaches to our understanding of lung disease.
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PMID:Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling? 1706 73

Angiotensin (Ang) II plays a pivotal role in vascular fibrosis, which leads to serious complications in hypertension and diabetes. Connective tissue growth factor (CTGF) is a potent profibrotic factor implicated in the Ang II-induced pathologic fibrosis process. PPAR-gamma activators thiazolidinediones have been recently reported to have beneficial vascular effects. However, their effects and related molecular mechanisms on extracellular matrix (ECM) turnover in vascular smooth muscle cells (VSMCs) are unknown. The present study evaluated the regulation of Ang II-induced CTGF, ECM production and cell growth by rosiglitazone in VSMCs. In aorta of Ang II-infused rats, CTGF expression was markedly increased, and type III collagen and fibronectin overexpression was observed. Cotreatment with rosiglitazone diminished these changes, whereas increased nuclear PPAR-gamma expression in VSMCs. In growth-arrested VSMCs, rosiglitazone attenuated the proliferation and apoptosis, increased PPAR-gamma production and activation, and reduced CTGF and ECM production in response to Ang II in a dose-dependent fashion. These inhibitory effects were attenuated by the pretreatment of cells with PPAR-gamma antagonist GW9662 or bisphenol A diglycidyl ether (BADGE). Furthermore, rosiglitazone inhibited Ang II-induced Smad2 production and phosphorylation but had no effect on transforming growth factor-beta(1) (TGF-beta(1)) expression. These results suggest that in Ang II-stimulated VSMCs, rosiglitazone caused an antiproliferative, antiapototic effect and reduces ECM production through mechanisms that include reducing CTGF expression, and a crosstalk between PPAR-gamma and Smad may be involved in the inhibitory effects of rosiglitazone. This novel finding suggests a role of PPAR-gamma activators in preventing Ang II-induced vascular fibrosis.
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PMID:Rosiglitazone inhibits angiotensin II-induced CTGF expression in vascular smooth muscle cells - role of PPAR-gamma in vascular fibrosis. 1707 4

Insulin resistance is a characteristic feature of cardiovascular and renal diseases, and angiotensin II (Ang II) has been suggested to induce insulin resistance. The aims of this study were to elucidate the effect of chronic Ang II infusion on vascular reactivity and organ damage in insulin-sensitive rats. We confirmed the following three points. First, there was no significant difference in pressor response to chronic Ang II infusion (600 ng/kg/min) between insulin-sensitive transgenic rats (Tg) and control rats (C). Second, there was no significant difference in cardiac hypertrophy and fibrosis by chronic Ang II infusion between the two groups. However, third, fibrotic response to chronic Ang II infusion evaluated by histopathological scoring in the kidney was significantly decreased in insulin-sensitive transgenic rats (renal fibrosis and nephropathy score: C+Ang II vs Tg+Ang II; 2.5 vs 1.3; p<0.05). Furthermore, the expression of TGF-beta, a fibrosis indicator, was also significantly suppressed in the kidneys of the transgenic rats (TGF-beta1/GAPDH ratio: C+Ang II vs Tg+Ang II; 1.15 vs 0.81; p<0.05). This result indicates that the growth hormone/insulin-like growth factor-1 axis is critically involved in the development of renal injury and fibrosis, rather than hypertension, cardiac hypertrophy, and cardiac fibrosis induced by chronic Ang II administration.
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PMID:Fibrotic response to angiotensin II is blunted in the kidney, but not in the heart, in insulin-sensitive long-lived transgenic dwarf rats. 1714 44


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