Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Secretion of prorenin from extrarenal tissues comprises approximately half of the renin protein in plasma; its origin is unknown. The discovery of a prorenin/renin receptor that activates vascular tissue kinases raises interest in this otherwise inactive component. We have studied its glycosylation as this may distinguish it from renal renin. The binding of renin protein (active and prorenin) in human plasma and tissues to concanavalin (Con A) and wheat germ lectins was deployed. Immunoradiometric and enzyme kinetic assays were applied to column fractions. Mannosylated renin protein binds to Con A and has been shown to be taken up by human vascular and hepatic cells on mannose-6-phosphate receptors, possibly as a clearance mechanism. But the other binding sites of prorenin/renin that elicit a cellular phosphorylation response are apparently independent of glycosylation. The tissues examined (kidney, adrenal, ovary) each contain high proportions of Con A binding renin, but the plasma of normal resting males and females contain mainly non-binding renin, the proportion increasing as renal renin secretion decreases. The extreme of this relationship is seen in anephric patients and in some normal women on oral contraceptives with suppressed renal renin, in whom plasma renin is entirely non-binding to Con A. Conversely, when renal renin secretion was stimulated, the increased plasma active renin bound to Con A. However, extrarenal tissues containing exclusively Con A non-binding renin protein, and hence potential sources of anephric plasma renin protein, were not identified, but are unlikely to include adrenal or female reproductive tract. The findings are consistent with the view that normal human plasma contains a considerable amount of amannosylated prorenin of extrarenal origin that escapes hepatic clearance and has a longer half-life than renal renin. This plasma renin form would be expected to be activated in association with the recently described renin/prorenin aspartyl protease receptor and to participate in local pathophysiological processes.
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PMID:Lectin chromatography of extrarenal renin protein in human plasma and tissues: potential endocrine function via the renin receptor. 1580 37

Recent evidence suggesting a strong interplay between components of the renin-angiotensin system and key mediators of fibrosis led us to hypothesize that renin, independent of its enzymatic action to enhance angiotensin (Ang) II synthesis, directly increases production of the fibrogenic cytokine transforming growth factor (TGF)-beta. Human or rat mesangial cells (MCs) were treated with human recombinant renin (HrRenin) or rat recombinant renin (RrRenin) and the effects on TGF-beta1, plasminogen activator inhibitor-type 1 (PAI-1), fibronectin (FN) and collagen 1 mRNA and protein were investigated. Blockade of the rat MC renin receptor was achieved using siRNA. HrRenin or RrRenin, at doses shown to be physiologically relevant, induced marked dose- and time-dependent increases in TGF-beta1. These effects were not altered by adding an inhibitor of renin's enzymatic action (RO 42-5892), the Ang II receptor antagonist losartan or the Ang-converting enzyme inhibitor enalapril. RrRenin also induced PAI-1, FN and collagen 1 mRNA and PAI-1 and FN protein in a dose-dependent manner. Neutralizing antibodies to TGF-beta partially blocked these effects. Supernatant and cell lysate Ang I and Ang II levels were extremely low. MC angiotensinogen mRNA was undetectable both with and without added renin. Targeting of the rat renin receptor mRNA with siRNA blocked induction of TGF-beta1. We conclude that renin upregulates MC TGF-beta1 through a receptor-mediated mechanism, independent of Ang II generation or action. Renin-induced increases in TGF-beta1 in turn stimulate increases in PAI-1, FN and collagen I. Thus, renin may contribute to renal fibrotic disease, particularly when therapeutic Ang II blockade elevates plasma renin.
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PMID:Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. 1637 16

Recently, a receptor for renin was described that may be important for vascular uptake and activation of (pro)renin, thus leading to local generation of angiotensin II. To assess the in vivo relevance of this protein, we generated transgenic rats overexpressing the human renin receptor gene in smooth muscle tissue, under the control of a 16-kb fragment of the mouse smooth muscle myosin heavy chain gene [TGR(SMMHC-HRR)]. Four lines of transgenic animals were obtained. The correct pattern of expression of the transgene was confirmed by RNase protection assay and in situ hybridization. TGR(SMMHC-HRR) rats are fertile and develop normally. After 6 months of age, transgenic rats develop a cardiovascular phenotype with an elevated systolic blood pressure (137.8+/-5 versus 118.9+/-3.7 mm Hg; P=0.008), and an augmentation in heart rate (349.1+/-7.7 versus 303.1+/-16.16 bpm; P=0.023) in TGR(SMMHC-HRR) and controls, respectively. These alterations are progressively increasing with aging. Although kidney function and plasma renin were normal in TGR(SMMHC-HRR), an increase in plasma aldosterone [TGR(SMMHC-HRR) 428+/-64.9 versus 207.3+/-73.24 pg/mL in control; P=0.02] and in aldosterone/renin ratio [TGR(SMMHC-HRR) 8.04+/-2.2 versus 2.8+/-0.55 in control; P=0.03] was observed. This suggests that renin receptor overexpression has resulted in increased intraadrenal angiotensin II, thereby provoking enhanced aldosterone generation in the absence of changes in plasma renin. The rise in aldosterone may underlie, at least in part, the observed cardiovascular phenotype of TGR(SMMHC-HRR).
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PMID:Elevated blood pressure and heart rate in human renin receptor transgenic rats. 1640 65

Interaction between the renin-angiotensin system and cyclooxygenases in the kidney regulates renal microcirculation. Activation of the (pro)renin receptor has profibrotic effects, and now Kaneshiroet al. show that it also increases COX-2 synthesis. These results may have therapeutic implications, as blocking (pro)renin-receptor interaction would prevent the increase of angiotensin generation and prostaglandin synthesis, two phenomena underlying the pathogenesis of diabetic nephropathy.
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PMID:Increased cyclooxygenase-2, hyperfiltration, glomerulosclerosis, and diabetic nephropathy: put the blame on the (pro)renin receptor? 1680 42

Tissue accumulation of circulating prorenin results in angiotensin generation, but could also, through binding to the recently cloned (pro)renin receptor, lead to angiotensin-independent effects, like p42/p44 mitogen-activated protein kinase (MAPK) activation and plasminogen-activator inhibitor (PAI)-1 release. Here we investigated whether prorenin exerts angiotensin-independent effects in neonatal rat cardiomyocytes. Polyclonal antibodies detected the (pro)renin receptor in these cells. Prorenin affected neither p42/p44 MAPK nor PAI-1. PAI-1 release did occur during coincubation with angiotensinogen, suggesting that this effect is angiotensin mediated. Prorenin concentration-dependently activated p38 MAPK and simultaneously phosphorylated HSP27. The latter phosphorylation was blocked by the p38 MAPK inhibitor SB203580. Rat microarray gene (n=4800) transcription profiling of myocytes stimulated with prorenin detected 260 regulated genes (P<0.001 versus control), among which genes downstream of p38 MAPK and HSP27 involved in actin filament dynamics and (cis-)regulated genes confined in blood pressure and diabetes QTL regions, like Syntaxin-7, were overrepresented. Quantitative real-time RT-PCR of 7 selected genes (Opg, Timp1, Best5, Hsp27, pro-Anp, Col3a1, and Hk2) revealed temporal regulation, with peak levels occurring after 4 hours of prorenin exposure. This regulation was not altered in the presence of the renin inhibitor aliskiren or the angiotensin II type 1 receptor antagonist eprosartan. Finally, pilot 2D proteomic differential display experiments revealed actin cytoskeleton changes in cardiomyocytes after 48 hours of prorenin stimulation. In conclusion, prorenin exerts angiotensin-independent effects in cardiomyocytes. Prorenin-induced stimulation of the p38 MAPK/HSP27 pathway, resulting in alterations in actin filament dynamics, may underlie the severe cardiac hypertrophy that has been described previously in rats with hepatic prorenin overexpression.
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PMID:Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II. 1694 Feb 9

Hypertension is often associated clinically with diabetes as part of the insulin-resistance syndrome or as a manifestation of renal disease. Elevated systemic blood pressure accelerates micro- and macrovascular complications in diabetes. Vasoactive hormone pathways including the renin-angiotensin-aldosterone system (RAAS) appear to play a pivotal role in the pathogenesis and progression of diabetic complications and possible diabetes itself. Recent studies have increased our understanding of the complexity of the RAAS with identification of new components of this cascade including angiotensin-converting enzyme 2 and a putative renin receptor. Agents that interrupt the RAAS confer end-organ protection in diabetes via hemodynamic and non-hemodynamic mechanisms. Trials are investigating the possible role of RAAS blockade in the prevention of type 2 diabetes.
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PMID:Hypertension and diabetes: role of the renin-angiotensin system. 1695 81

It is generally assumed that the beneficial effects of renin-angiotensin system blockers in cardiovascular disease are due to blockade of the generation or action of angiotensin at tissue sites. Such generation depends on the uptake of renin and/or its inactive precursor prorenin from the circulation. Recently, a (pro)renin receptor has been cloned that might perform this task. Unexpectedly, this receptor also induced angiotensin-independent effects, suggesting that renin and/or prorenin may act as agonists for this receptor. Ultimately, this could lead to the development of (pro)renin receptor blockers (i.e., drugs that not only prevent tissue angiotensin generation but also inhibit renin- or prorenin-induced effects).
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PMID:The (pro)renin receptor: therapeutic consequences. 1698 89

When the 'handle region' of the prorenin prosegment interacts with the (pro)renin receptor, the prorenin molecule partially changes the conformation to an enzymatically active state. On the other hand, the receptor triggers its own intracellular signalling pathways independent of the renin-angiotensin system (RAS). The 'handle region' peptide competitively binds to the receptor as a decoy peptide and inhibits both the non-proteolytic activation of prorenin and the RAS-independent intracellular signals. Therefore, prorenin receptor blockers including the decoy peptide may have superior benefits on end-organ damage in diabetes and hypertension compared with conventional RAS inhibitors.
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PMID:Prorenin receptor blockers: effects on cardiovascular complications of diabetes and hypertension. 1698 90

To clarify the mechanism of the effects of angiotensin II AT(1) receptor antagonists on adipose tissue, we treated 8 week-old male Wistar Kyoto rats with the angiotensin II AT(1) receptor antagonist Candesartan cilexetil (10 mg/kg/day) for 18 weeks. Candesartan cilexetil reduced body weight gain, decreased fat tissue mass due to hypotrophy of epididymal and retroperitoneal adipose tissue and decreased adipocyte size without changing the number of adipocytes. Candesartan cilexetil decreased serum leptin levels and epididymal leptin mRNA, increased serum adiponectin levels and epididymal adiponectin mRNA, decreased epididymal tumor necrosis factor alpha (TNFalpha) mRNA, and increased fatty acid synthase mRNA. Considered free of peroxisome proliferator-activated receptor gamma (PPARgamma) agonist activity, Candesartan cilexetil increased epididymal expression of PPARgamma mRNA. The effects of Candesartan cilexetil on adipokine production and release may be attributable to PPARgamma activation and/or decrease in adipocyte cell size. In addition, Candesartan cilexetil treatment increased the expression of epididymal angiotensin II AT(2) receptor mRNA and protein and decreased the expression of renin receptor mRNA. These results suggest that Candesartan cilexetil influences lipid metabolism in adipose tissue by promoting adipose tissue rearrangement and modulating adipokine expression and release. These effects are probably consequences of local angiotensin II AT(1) receptor inhibition, angiotensin II AT(2) receptor stimulation, and perhaps additional angiotensin II-independent mechanisms. Our results indicate that the activity of local renin-angiotensin system plays an important role in adipose tissue metabolism. The decrease in the pro-inflammatory cytokine TNFalpha and the increase in the anti-inflammatory adipokine adiponectin indicate that Candesartan cilexetil may exert significant anti-inflammatory properties.
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PMID:Long-term angiotensin II AT1 receptor inhibition produces adipose tissue hypotrophy accompanied by increased expression of adiponectin and PPARgamma. 1706 84

Adipose tissue synthesizes all components of the renin-angiotensin system. The renin receptor (RenR) is able, on renin binding, to increase its efficiency to generate angiotensin I from angiotensinogen. We demonstrate that RenR is specifically synthesized in the stromal portion of human adipose tissue in both isolated interadipocyte stromal cells and in stromal areas. RenR is expressed at the periphery of cells, strongly suggesting a membranal localization. RenR protein expression in primary cultures of human stromal cells decreased significantly during differentiation, whereas RenR mRNA levels did not change, demonstrating that RenR was expressed in both preadipocyte and nonpreadipocyte cells, and was regulated at a posttranscriptional level. Double-labeling immunohistochemistry of human adipose tissue sections revealed that RenR was colocalized with renin, whereas incubation of 3T3-L1, a preadipocyte cell line, with renin stimulated the phosphorylation state of the intracellular signaling pathway ERK 1/2, and short exposure of human adipose stromal cells in primary culture to renin was followed by a long-lasting dose-dependent increase of angiotensin I generation, indicating that adipose RenR is functional. We show, using a large set of human adipose tissue biopsies, that RenR expression was increased in visceral compared with subcutaneous adipose tissue of lean and obese patients. Taken together with our finding that RenR was colocalized with plasminogen activator inhibitor type 1, the main inhibitor of the fibrinolytic system in visceral adipose tissue, the above-mentioned data suggest that RenR plays a role in obesity-induced visceral adipose tissue accumulation and its accompanying cardiovascular complications.
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PMID:Renin receptor expression in human adipose tissue. 1719 44


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