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)

Renin plays a critical role in fluid and electrolyte homeostasis by cleaving angiotensinogen to produce Ang peptides. Whilst it has been demonstrated that renin mRNA is expressed in the brain, the distribution of cells responsible for this expression remains uncertain. We have used a transgenic mouse approach in an attempt to address this question. A transgenic mouse, in which a 12.2 kb fragment of the human renin promoter was used to drive expression of Cre-recombinase, was crossed with the ROSA26-lac Z reporter mouse strain. Cre-recombinase mediated excision of the floxed stop cassette resulted in expression of the reporter protein, beta-galactosidase. This study describes the distribution of beta-galactosidase in the brain of the crossed transgenic mouse. In all cases where it was examined the reporter protein was co-localized with the neuronal marker NeuN. An extensive distribution was observed with numerous cells labeled in the somatosensory, insular, piriform and retrosplenial cortices. The motor cortex was devoid of labeled cells. Several other regions were labeled including the parts of the amygdala, periaqueductal gray, lateral parabrachial nucleus and deep cerebellar nuclei. Overall the distribution shows little overlap with those regions that are known to express receptors for the renin-angiotensin system in the adult brain. This transgenic approach, which demonstrates the distribution of cells which have activated the human renin promoter at any time throughout development, yields a unique and extensive distribution of putative renin-expressing neurons. Our observations suggest that renin may have broader actions in the brain and may indicate a potential for interaction with the (pro)renin receptor or production of a ligand for non-AT(1)/AT(2) receptors.
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PMID:Distribution of cells expressing human renin-promoter activity in the brain of a transgenic mouse. 1884 Apr 19

Morbidity and mortality of diabetes mellitus are strongly associated with cardiovascular disease including nephropathy. A discordant tissue renin-angiotensin system (RAS) might be a mediator of the endothelial dysfunction leading to both micro- and macrovascular complications of diabetes. The elevated plasma levels of prorenin in diabetic subjects with microvascular complications might be part of this discordant RAS, especially since the plasma renin levels in diabetes are low. Prorenin, previously thought of as an inactive precursor of renin, is now known to bind to a (pro)renin receptor, thus activating locally angiotensin-dependent and -independent pathways. In particular, the stimulation of the transforming growth factor-beta (TGF-beta) system by prorenin could be an important contributor to diabetic disease complications. This review discusses the concept of the prorenin-(pro)renin receptor-TGF-beta(1) axis, concluding that interference with this pathway might be a next logical step in the search for new therapeutic regimens to reduce diabetes-related morbidity and mortality.
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PMID:Diabetic complications: a role for the prorenin-(pro)renin receptor-TGF-beta1 axis? 1884 Apr 99

High plasma prorenin levels in diabetic patients predict microvascular complications, but the mechanism of the connection between these factors has remained unclear. (Pro)renin receptors were recently found in the human kidney, and their distribution in the kidneys include the mesangium and podocytes. The binding of prorenin to the (pro)renin receptor triggers two major pathways: the angiotensin II-dependent pathway as a result of the conversion of prorenin to the active form of prorenin through a conformational change, and the angiotensin II-independent, (pro)renin-receptor-dependent intracellular mitogen-activated protein kinase pathway. To investigate whether the (pro)renin-receptor-dependent pathways contribute to the pathophysiology of the end-organ damage that occurs in diabetes, the handle region peptide, which binds to the receptor and competitively inhibits prorenin from binding to the receptor, was administered to rats with streptozotocin-induced type I diabetes and to a model of type II diabetes, db/db mice. The handle region peptide significantly inhibited the development of end-organ damage in these diabetic animals, and had a greater benefit than angiotensin-converting enzyme inhibitors in diabetic angiotensin II-type 1a-receptor-deficient mice. In addition, the infusion of the handle region peptide in animals with streptozotocin-induced type I diabetes significantly regressed the nephropathy that had already occurred. These results suggest that prorenin and the (pro)renin receptor play a pivotal role in the pathophysiology of diabetic nephropathy. Receptor-bound prorenin may prove useful as an important therapeutic target for the prevention and regression of end-organ damage in patients with diabetes.
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PMID:Activated prorenin as a therapeutic target for diabetic nephropathy. 1892 97

Discovery of prorenin/renin, or (pro)renin, receptor uncovered a novel function of (pro)renin as receptor ligand in addition to enzyme and its precursor; the same receptor was shown to promote reversible activation of prorenin and enhance the enzyme activity of mature renin. Stimulating the receptor activates mitogen-activated protein kinase and hypertrophic, hyperplastic, profibrotic, and cyclooxygenase-2-activating signals. These receptor signals were transmitted independently of angiotensin (Ang) II receptor. A specific blocker of the receptor was discovered-a peptide segment in prorenin that binds to the receptor and blocks ligand binding. Its infusion in animal models of hypertension and diabetes not only prevented nephropathy and cardiac hypertrophy, but also caused regression of nephropathy, whereas Ang II receptor gene deletion and angiotensin-converting enzyme inhibition merely delayed the onset or ameliorated pathologic phenotypes. These results suggest that (pro)renin receptor is responsible for end-organ damage.
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PMID:Prorenin/renin receptor, signals, and therapeutic efficacy of receptor blocker in end-organ damage. 1893 83

The receptor-associated prorenin system (RAPS) refers to pathogenic mechanisms whereby prorenin binding to its receptor activates both the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling pathways. Although we found significant involvement of angiotensin II type 1 receptor (AT1-R)-mediated inflammation in choroidal neovascularization (CNV), a central abnormality of vision-threatening age-related macular degeneration, the association of receptor-associated prorenin system with CNV has not been defined. Here, (pro)renin receptor blockade in a murine model of laser-induced CNV led to the significant suppression of CNV together with macrophage infiltration and the up-regulation of intercellular adhesion molecule-1, (ICAM-1) monocyte chemotactic protein-1, (MCP-1) vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2. To clarify the role of signal transduction via the (pro)renin receptor in CNV, we used mice in which renin-angiotensin system was deactivated by either the pharmacological blockade of AT1-R with losartan or the genetic ablation of AT1-R or angiotensinogen. Compared with wild-type controls, these mice exhibited significant reduction of CNV and macrophage infiltration, both of which were further suppressed by (pro)renin receptor blockade. The (pro)renin receptor and phosphorylated extracellular signal-regulated kinases (ERK) were co-localized in vascular endothelial cells and macrophages in CNV. (Pro)renin receptor blockade suppressed ERK activation and the production of MCP-1 and VEGF, but not ICAM-1, VEGFR-1, or VEGFR-2, in AT1-R-deficient mice with CNV and in losartan-treated microvascular endothelial cells and macrophages. These results indicate the significant contribution of RAPS to CNV pathogenesis.
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PMID:(Pro)renin receptor promotes choroidal neovascularization by activating its signal transduction and tissue renin-angiotensin system. 1897 4

Previously we demonstrated that upstream stimulatory factor 2 (USF2) transgenic (Tg) mice developed nephropathy including albuminuria and glomerular hypertrophy, accompanied by increased transforming growth factor (TGF)-beta and fibronectin accumulation in the glomeruli. However, the mechanisms by which overexpression of USF2 induces kidney injury are unknown. USF has been shown to regulate renin expression. Moreover, the renin-angiotensin system (RAS) plays important roles in renal diseases. Therefore, in the present studies the effects of USF2 on the regulation of RAS in the kidney as well as in mesangial cells from USF2 (Tg) mice were examined. The role of USF2-mediated regulation of RAS in TGF-beta production in mesangial cells was also determined. Our data demonstrate that USF2 (Tg) mice exhibit increased renin and angiotensin (ANG) II levels in the kidney. In contrast, renal expression of other components of RAS such as renin receptor, angiotensinogen, angiotensin-converting enzyme (ACE), ACE2, angiotensin type 1a (AT(1a)) receptor, and AT(2) receptor was not altered in USF2 (Tg) mice. Similarly, mesangial cells isolated from USF2 (Tg) mice had increased renin and ANG II levels. Mesangial cells overexpressing USF2 also had increased TGF-beta production, which was blocked by small interfering RNA-mediated renin gene knockdown or RAS blockade (enalapril or losartan). Collectively, these results suggest that USF2 promotes renal renin expression and stimulates ANG II generation, leading to activation of the intrarenal RAS. In addition, renin-dependent ANG II generation mediates the effect of USF2 on TGF-beta production in mesangial cells, which may contribute to the development of nephropathy in USF2 (Tg) mice.
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PMID:Activation of renal renin-angiotensin system in upstream stimulatory factor 2 transgenic mice. 1900 31

Vitamin D receptor (VDR) activation has a beneficial influence on the progression of experimental renal insufficiency, and reduced renal tissue renin expression may play a role in this process. Freundlich and co-workers now report that VDR activation also suppresses the expression of angiotensinogen, angiotensin II type 1 receptor, and renin receptor in the kidneys of 5/6 nephrectomized rats, effects associated with reduced blood pressure and urinary protein excretion and with alleviated renal tissue damage.
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PMID:Expanding targets of vitamin D receptor activation: downregulation of several RAS components in the kidney. 1881 85

Discovery of the (pro)renin receptor uncovered a novel function of renin/prorenin as the receptor ligands in addition to the enzyme and its precursor. The bindings of renin and prorenin to the (pro)renin receptor trigger two major pathways: the angiotensin II-dependent pathway as a result of the enzymatic activation of renin/prorenin and the angiotensin II-independent intracellular pathway involving hypertrophic, hyperplastic, and profibrotic signals. A specific blocker of the receptor was discovered through identification of the amino acid sequence of prorenin prosegment that binds to the receptor and leads to non-proteolytic conversion of prorenin to its active form. A peptide containing this sequence was found to block the binding of prorenin to its receptor. Its infusion in animal models of diabetes and low-renin hypertension significantly inhibited the development and progression of nephropathy, but (pro)renin receptor blockade had no benefit in the clipped kidney of 2K1C rats or rat models of high-renin hypertension. Since renin is still active without a (pro)renin receptor, (pro)renin-receptor blockade elicits a maximum benefit under low-renin conditions. Thus, (pro)renin-receptor blockade can be a useful therapy for chronic kidney disease with low renin levels in the plasma.
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PMID:Drug discovery for overcoming chronic kidney disease (CKD): new therapy for CKD by a (pro)renin-receptor-blocking decoy peptide. 1915 36

Renin initiates angiotensin II formation and has no other known functions. We observed that transgenic rats (TGR) overexpressing the human renin gene (hREN) developed moderate obesity with increased body fat mass and glucose intolerance compared with nontransgenic Sprague-Dawley (SD) rats. The metabolic changes were not reversed by an angiotensin-converting enzyme inhibitor, a direct renin inhibitor, or by (pro)renin receptor blocker treatment. The obese phenotype in TGR(hREN) originated from higher food intake, which was partly compensated by increases in resting energy expenditure, total thermogenesis (postprandial and exercise activity), and lipid oxidation during the first 8 weeks of life. Once established, the difference in body weight between TGR(hREN) and SD rats remained constant over time. When restricted to the caloric intake of SD, TGR(hREN) developed an even lower body weight than nontransgenic controls. We did not observe significant changes in the cocaine and amphetamine-regulated transcript, pro-opiomelanocortin, both anorexigenic, or neuropeptide Y, orexigenic, mRNA levels in TGR(hREN) versus SD controls. However, the mRNA level of the agouti-related peptide, orexigenic, was significantly reduced in TGR(hREN) versus SD controls at the end of the study, which indicates a compensatory mechanism. We suggest that the human renin transgene initiates a process leading to increased and early appetite, obesity, and metabolic changes not related to angiotensin II. The mechanisms are independent of any currently known renin-related effects.
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PMID:Energy metabolism in human renin-gene transgenic rats: does renin contribute to obesity? 1917 93

While the renin-angiotensin system (RAS) is widely recognized to be involved in atherosclerosis, its potential role in the progression from atherosclerotic lesions to abdominal aortic aneurysm (AAA) is poorly understood. The present study aimed to investigate which components of the RAS may render the atherosclerotic aorta aneurysmatic. The expression of renin, prorenin/renin receptor, angiotensinogen, AT1- and AT2 receptors, cathepsin D, cathepsin G and chymase was examined by immunoblotting and immunohistochemistry in human atherosclerotic, aneurysmatic and healthy aortic tissues obtained from patients undergoing elective repair or at autopsy. AT1- and AT2 receptor mRNA expression was determined using quantitative real-time RT-PCR. All investigated local RAS components were up-regulated in atherosclerotic as compared to healthy tissues. AAA compared to atherosclerosis was characterized by a further increase in the expression of all RAS components except for the AT2 receptor. Cathepsin D was exclusively up-regulated in AAA. Most RAS components co-localized with infiltrating leukocytes or mast cells pointing to their contribution to inflammatory processes. Due to their proteolytic features, some RAS components (cathepsin D and cathepsin G and chymase) may contribute to AAA formation by accessory mechanisms. Taken together, our data suggest that in humans, RAS activation is not just a key-player in the pathogenesis of atherosclerosis, but that a further increasing activation may be involved in the transition from atherosclerosis to AAA.
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PMID:Transition from atherosclerosis to aortic aneurysm in humans coincides with an increased expression of RAS components. 1919 79


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