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)

Endothelins (ETs) are 21-amino-acid peptides produced in many cells and tissues. The vascular ET system is represented mainly by ET-1 produced in endothelial cells. PreproET-1 gene expression is regulated by transactivating signals dependent on cooperative interaction of GATA-2 and AP-1 sites. ProET-1 is acted on by a furin-like enzyme to generate big ET-1, a 38-39-amino-acid peptide, which is converted to the mature 21-amino-acid peptide ET-1 by ET-converting enzyme (ECE) in endothelial cells, both intracellularly and on the cell membrane, and on the surface of underlying smooth muscle cells. The mature peptide ET-1 acts in a paracrine manner on smooth muscle cell ET(A) and ET(B) receptors to induce contraction and growth, and in an autocrine or paracrine manner on endothelial cells to induce production of the vasorelaxant and growth-inhibitory agents nitric oxide (NO) and prostacyclin. ET receptors are G-protein-coupled, resulting in activation of phospholipase C and generation of two second messengers, inositol triphosphate and diacylglycerol, which respectively stimulate calcium release and protein kinase C activation. Phospholipase D activation with generation of diacylglycerol, phospholipase A2 stimulation with release of arachidonic acid, activation of the Na+/H+ exchanger, and activation of tyrosine kinases and MAP kinases, are other pathways that contribute to contraction and growth induced by ET receptor stimulation. ET receptors may be downregulated by ET, especially under conditions in which large amounts of ET are being produced in the vasculature. This has been demonstrated in some models of experimental hypertension and in some forms of human hypertension. Some of the effects of angiotensin II, particularly growth of the smooth muscle media of blood vessels, have been shown under some conditions to be mediated by ET-1 via ET(A) receptors. Many ET-induced effects on smooth muscle cells can be blocked by ET(A)-selective ET antagonists, which makes possible an identification of the physiologic and pathophysiologic roles of the ET system in cardiovascular diseases such as hypertension, heart failure, atherosclerosis, coronary heart disease, restenosis after angioplasty, primary pulmonary hypertension, and other pathologic conditions.
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PMID:Vascular biology of endothelin. 988 41

This study was conducted to analyze the trend of histopathologic subtypes in idiopathic nephrotic syndrome (INS) in a homogenous racial group in India population. A prospective analysis of 400 consecutive children with INS was performed. Kidney biopsies were performed according to standard indications. Steroids were administered following the Arbeitsgeminschaft fur Padiatrische Nephrologie protocol. Cyclophosphamide was administered to children in the frequent-relapser, steroid-dependent, and steroid-nonresponder categories. Of the various histopathologic subtypes, focal segmental glomerulosclerosis (FSGS) was the most common (87 of 222 subtypes; 39.1%). Children who underwent biopsy between July 1992 and December 1996 (group B, n = 157) were compared with our initial published data of biopsies performed between January 1990 and June 1992 (group A, n = 65), with similar indications for biopsy in both groups. The incidence of FSGS was significantly greater in biopsies performed in the recent period (group B, 47% versus group A, 20%; P = 0.0002). The different clinical and biochemical parameters were also analyzed to differentiate FSGS from the other 2 subtypes. Hypertension (P = 0. 005), renal insufficiency at presentation (P = 0.001), and steroid resistance (P = 0.0006) were significantly greater in children with FSGS. On follow-up (mean, 5.4 years), children with FSGS were at a significantly greater risk for developing renal insufficiency (P = 0. 0001). We conclude there is a shift toward an increasing prevalence of FSGS over the years in the Indian population. This trend has immense therapeutic and prognostic significance.
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PMID:Changing trends of histopathology in childhood nephrotic syndrome. 1051 44

We have recently demonstrated that furin, PC5, and PC7, members of the subtilisin/kexin-like mammalian proprotein convertases (PCs), are found in rodent aorta. These PCs have been identified to activate several growth factors, adhesion molecules and extracellular matrix compounds by endoproteolytic cleavage. In the present study, we investigated the regulation of PC5 in vascular smooth muscle cells (VSMCs) in vitro and in vivo. Stimulation of rat aortic VSMCs with platelet-derived growth factor (PDGF)-BB (20 ng/mL), angiotensin II (Ang II, 1 micromol/L), or 10% fetal calf serum (FCS) for 48 hours increased DNA synthesis, as assessed by proliferating cell nuclear antigen (PCNA) immunoblotting. PC5 was strongly upregulated by PDGF-BB and 10% FCS (both 8-fold, P<0.05), whereas Ang II had no effect on PC5 protein levels compared with controls. The PCs furin and PC7, which display a comparable subcellular localization and cleavage activity, were found in VSMCs, but their levels did not increase following PDGF-BB, Ang II, or FCS stimulation. Time-course analysis revealed a rapid increase in PC5 levels after 30 minutes of PDGF-stimulation of VSMCs. PDGF-stimulated PC5 induction was inhibited by the PI3-kinase inhibitor wortmannin, and by rapamycin, an inhibitor of mTOR/p70(s6)-kinase (both P<0.05). In contrast, the mitogen-activated protein kinase (MAPK)-pathway inhibitor PD98059 did not inhibit PDGF-stimulated PC5 induction. Immunocytochemistry and in situ hybridization revealed low PC5 protein and mRNA levels in intact rat aorta in vivo. After balloon injury, PC5 protein and mRNA levels were strongly increased in proliferating PCNA-positive VSMCs. The present data demonstrate that PC5 is upregulated during proliferation of VSMCs in vivo and in vitro. We show that PDGF-induced PC5 expression is PI3-kinase/p70(s6)-kinase dependent. Thus, growth factors regulate the proprotein convertase PC5, which may play an important role during VSMC growth.
Hypertension 2002 Feb
PMID:Proprotein convertase PC5 regulation by PDGF-BB involves PI3-kinase/p70(s6)-kinase activation in vascular smooth muscle cells. 1188 80

The recent development of endothelin-1 (ET-1) antagonists and their potential use in the treatment of human disease raises questions as to the role of ET-1 in the pathophysiology of such cardiovascular ailments as hypertension, heart failure, renal failure and atherosclerosis. It is still unclear, for example, whether activation of an endogenous ET-1 system is itself the primary cause of any of these ailments. In that context, the phenotypic manifestations of chronic ET-1 overproduction may provide clues about the tissues and systems affected by ET-1. We therefore established two lines of transgenic mice overexpressing the ET-1 gene under the direction of its own promoter. These mice exhibited low body weight, diminished fur density and two- to fourfold increases in the ET-1 levels measured in plasma, heart, kidney and aorta. There were no apparent histological abnormalities in the visceral organs of young (8 weeks old) transgenic mice, nor was their blood pressure elevated. In aged (12 months old) transgenic mice, however, renal manifestations, including prominent interstitial fibrosis, renal cysts, glomerulosclerosis and narrowing of arterioles, were detected. These pathological changes were accompanied by decreased creatinine clearance, elevated urinary protein excretion and salt-dependent hypertension. It thus appears that mild, chronic overproduction of ET-1 does not primarily cause hypertension but triggers damaging changes in the kidney which lead to the susceptibility to salt-induced hypertension.
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PMID:Renal damage and salt-dependent hypertension in aged transgenic mice overexpressing endothelin-1. 1190 42

PACE (Physician-based Assessment and Counseling for Exercise) is an individualized theory-based minimal intervention strategy aimed at the enhancement of regular physical activity. The aim of this study was to evaluate the effectiveness of a PACE intervention applied by general practitioners (GPs) on potential determinants of physical activity. A randomized controlled trial was conducted in 29 general practices with the following inclusion criteria for patients: aged between 18 and 70 years, diagnosed with hypertension, hypercholesterolemia and/or non-insulin-dependent diabetes mellitus, and not in maintenance stage for regular physical activity. The intervention consisted of two visits with the GP and two telephone booster calls by a physical activity counselor. Determinants of physical activity were assessed with questionnaires at baseline, and at 8-week (short), 6-month (medium) and 1-year (long) follow-up. A significant positive effect was observed on self-efficacy, and on the use of cognitive and behavioral processes of change, at both short- and medium-term follow-up. The intervention respondents also perceived fewer barriers for regular physical activity at short-term and used behavioral processes of change more at long-term follow-up. No intervention effect was observed for perceived benefits of physical activity. In conclusion, this GP-based PACE intervention resulted in positive changes in potential determinants of physical activity.
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PMID:The positive effect on determinants of physical activity of a tailored, general practice-based physical activity intervention. 1547 5

Corticosteroids are still a cornerstone in the immunosuppressive regimen in pediatric renal transplant recipients despite their numerous side effects, such as inhibition of longitudinal growth, body disfigurement, arterial hypertension, cardiovascular complications, osteopathy, and others. Previous attempts to spare steroids in cyclosporine (CsA)-based protocols have been associated with an increased risk for acute rejection episodes. The recent introduction of more-potent immunosuppressive medications, such as mycophenolate mofetil (MMF), have, however, renewed interest in steroid-sparing protocols to avoid or ameliorate steroid-associated side effects. Recent studies in Caucasian adult renal transplant recipients receiving CsA and MMF have shown a beneficial effect of late (>/=6 months post transplant) steroid withdrawal on steroid-associated side effects without the burden of an increased rate of acute rejection episodes. These favorable results compared with previous reports in patients on CsA and azathioprine (AZA) can be ascribed to the higher immunosuppressive potency of MMF compared with AZA. We have shown in a retrospective case control study in 40 pediatric renal transplant recipients that late steroid withdrawal is safe and successful in stable patients under an immunosuppressive maintenance therapy with CsA and MMF. The Mid-European Study Group on Pediatric Renal Transplantation and the Arbeitsgemeinschaft fur Padiatrische Nephrologie are currently performing a prospective randomized trial to validate these observations.
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PMID:Steroid withdrawal in pediatric and adult renal transplant recipients. 1565 Aug 83

TGF-beta proteins are main regulators of blood vessel development and maintenance. Here, we report an unprecedented link between TGF-beta signaling and arterial hypertension based on the analysis of mice mutant for Emilin1, a cysteine-rich secreted glycoprotein expressed in the vascular tree. Emilin1 knockout animals display increased blood pressure, increased peripheral vascular resistance, and reduced vessel size. Mechanistically, we found that Emilin1 inhibits TGF-beta signaling by binding specifically to the proTGF-beta precursor and preventing its maturation by furin convertases in the extracellular space. In support of these findings, genetic inactivation of Emilin1 causes increased TGF-beta signaling in the vascular wall. Strikingly, high blood pressure observed in Emilin1 mutants is rescued to normal levels upon inactivation of a single TGF-beta1 allele. This study highlights the importance of modulation of TGF-beta availability in the pathogenesis of hypertension.
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PMID:Emilin1 links TGF-beta maturation to blood pressure homeostasis. 1653 37

Hypertension is a serious medical problem affecting millions of people worldwide. A key protein regulating blood pressure is the Epithelial Na(+) Channel (ENaC). In accord, loss of function mutations in ENaC (PHA1) cause hypotension, whereas gain of function mutations (Liddle syndrome) result in hypertension. The region mutated in Liddle syndrome, called the PY motif (L/PPxY), serves as a binding site for the ubiquitin ligase Nedd4-2, a C2-WW-Hect E3 ubiquitin ligase. Nedd4-2 binds the ENaC-PY motif via it WW domains, ubiquitylates the channel and targets it for endocytosis, a process impaired in Liddle syndrome due to poor binding of the channel to Nedd4-2. This leads to accumulation of active channels at the cell surface and increased Na(+) (and fluid) absorption in the distal nephron, resulting in elevated blood volume and blood pressure. Compounds that destabilize cell surface ENaC, or enhance Nedd4-2 activity in the kidney, could potentially serve as drug targets for hypertension. In addition, recent discoveries of regulation of activation of ENaC by proteases such as furin, prostasin and elastase, which cleave the extracellular domain of this channel leading to it activation, as well as the identification of inhibitors that block the activity of these proteases, provide further avenues for drug targeting of ENaC and the control of blood pressure.
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PMID:ENaC and its regulatory proteins as drug targets for blood pressure control. 1869 Oct 17

The German Competence Network on Atrial Fibrillation (AFNET) is an interdisciplinary national research network funded by the Federal Ministry of Education and Research (BMBF) since 2003. The AFNET aims at improving treatment of atrial fibrillation (AF), the most frequent sustained arrhythmia of the heart. The AFNET has established a nationwide patient registry on manifestation, diagnostics, and therapy of AF in Germany. The data analyzed to date demonstrate that patients with AF are likely to have multiple comorbidities (hypertension, valvular heart disease, coronary artery disease, diabetes mellitus) and an advanced age. Regarding oral anticoagulation, guideline adherence is very high. Basic research has identified specific changes in atrial tissue during AF-induced remodeling providing the rationale for novel therapeutic interventions. Clinical trials are being carried out to optimize pharmacological and nonpharmacological treatments. The ANTIPAF trial is designed to prove that angiotensin II receptor blockers reduce the incidence of paroxysmal AF. The Flec-SL trial tests the efficacy of a short-term treatment with antiarrhythmic drugs after cardioversion. The Gap-AF trial investigates the impact of complete pulmonary vein (PV) isolation versus incomplete circumferential PV ablation on AF recurrences. The effect of preventive pacing on the recurrence of paroxysmal AF is studied in the BACE-PACE trial.
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PMID:The German Competence Network on Atrial Fibrillation (AFNET). 1913 44

The (pro)renin receptor [(P)RR] is a 35-kDa transmembrane protein that plays a pivotal role in angiotensin tissue generation and in nonproteolytic prorenin activation. We detected a soluble form of (P)RR [s(P)RR; 28 kDa] in the conditioned medium of cultured cells. The aims of our study were to identify the protease responsible for the generation of s(P)RR, the site of shedding, and to establish the existence of circulating s(P)RR in plasma. We identified furin as the protease responsible for the shedding of endogenous (P)RR based on the following: LoVo colon carcinoma cells devoid of active furin synthesize full-length (P)RR but do not secrete s(P)RR; transfection of Chinese hamster ovary cells with a plasmid coding for alpha1-antitrypsin Portland variant, an inhibitor of furin, completely inhibited the generation of s(P)RR, whereas addition of GM6001, an inhibitor of metalloproteases or of tumor necrosis factor-alpha protease inhibitor-1, an inhibitor of ADAM17, in the culture medium has no effect; when the cDNA coding for (P)RR was translated in vitro and incubated with recombinant furin or ADAM17, only furin was able to generate the 28 kDa-s(P)RR, and mutagenesis in the potential furin cleavage R275A/KT/R278A site abolished s(P)RR generation. Immunofluorescence study in glomerular epithelial cells showed that (P)RR was cleaved in the trans-Golgi, and coprecipitation experiments with renin showed that s(P)RR was present in plasma. In conclusion, our results show that s(P)RR is generated intracellularly by furin cleavage, and that s(P)RR detected in plasma is able to bind renin.
Hypertension 2009 Jun
PMID:Soluble form of the (pro)renin receptor generated by intracellular cleavage by furin is secreted in plasma. 1938 Jun 13


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