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

(Pro)renin receptor ((P)RR), a specific receptor for renin and prorenin, is a 350 amino-acid protein with a single transmembrane domain and may play important pathophysiological roles in diabetic nephropathy. The aim of the present study is to clarify the expression of (P)RR in the kidney with end-stage renal disease due to diabetic nephropathy. The kidney tissues were obtained at autopsy from patients with and without Type 2 diabetes mellitus (n=5 without diabetes mellitus; and n=8 with diabetes mellitus). Immunocytochemistry showed that (P)RR was mainly expressed in the tubular cells and collecting duct cells of the kidney without diabetic nephropathy. Cells in glomeruli were very weakly and sporadically immunostained for (P)RR. Vascular smooth muscle cells and endothelial cells were very weakly or were not immunostained for (P)RR. Adipocytes in the adipose tissue around the kidney were positively immunostained for (P)RR. Immunostaining pattern of (P)RR in the kidney with diabetic nephropathy was similar to that without diabetic nephropathy. However, most notably, (P)RR immunostaining in the tubular cells and collecting duct cells was clearly and frequently more strongly observed in the kidney with diabetic nephropathy up to the end-stage renal disease. The present study has raised the possibility that (P)RR expressed in the diabetic kidney may play a pathophysiological role in angiotensin I generation and renal fibrosis found in end-stage renal disease.
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PMID:Expression of (pro)renin receptor in human kidneys with end-stage kidney disease due to diabetic nephropathy. 2038 87

High plasma prorenin levels in diabetic patients predict microvascular complications, but the mechanism of the connection between them has remained unclear. (Pro)renin receptors were recently found in the human kidney, and their distribution in various organs, including the heart, has been identified. Binding of prorenin to the (pro)renin receptor triggers two major pathways: the angiotensin II-dependent pathway as a result of conversion of prorenin to the active form of prorenin by a conformational change, and the angiotensin II-independent intracellular pathway via the (pro)renin receptor. To investigate whether the (pro)renin-receptor-dependent pathways contribute to the pathophysiology of the end-organ damage that occurs in diabetes and hypertension, a (pro)renin receptor blocker (PRRB), which binds to the receptor and competitively inhibits prorenin binding to the receptor, was administered to rats with streptozotocin-induced diabetes and to stroke-prone spontaneously hypertensive rats. PRRB significantly inhibited the development and progression of end-organ damage in these animal models of diabetes and hypertension, and it was of greater benefit than conventional inhibitors in relation to the renin-angiotensin system in diabetic angiotensin II-type 1a-receptor-deficient mice. The (pro)renin receptor may prove useful as an important therapeutic target for the prevention and regression of end-organ damage in diabetes and hypertension.
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PMID:Critical roles of (pro)renin receptor-bound prorenin in diabetes and hypertension: sallies into therapeutic approach. 2040 80

The (pro)renin receptor [(P)RR] specifically binds renin and prorenin and mediates their intracellular effects. It acts as co-factor for renin and prorenin by increasing their enzymatic activity on the cell-surface and it activates the mitogen activated protein kinases ERK1/2 (extracellular signal regulated kinase) cascade leading to cell proliferation and to upregulation of profibrotic genes expression. Studies in genetically modified animals over-expressing ubiquitously (P)RR or specifically in smooth-muscle cells suggest a direct role for (P)RR cardiovascular and renal pathologies. A putative (P)RR blocker consisting in part of the prosegment of prorenin gave spectacular results in the prevention of diabetic nephropathy and cardiac fibrosis but its mechanism of action and its specificity for (P)RR remain controversial. Unexpectedly, the total ablation of (P)RR gene is impossible in contrast to the other components of the renin angiotensin system (RAS) and studies in zebra fish and in embryonic stem cells indicate that (P)RR is necessary to cell survival and proliferation. Furthermore, a mutation of (P)RR is associated with mental retardation and epilepsy, pointing to an essential role of (P)RR in brain development. If the role of (P)RR in cardiovascular and renal diseases can be confirmed in (P)RR knockout animals, the benefit of a (P)RR blocker in order to optimize the tissue RAS blockade should really be addressed but not without a good understanding of all its functions and not only those related to the RAS.
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PMID:Twenty years of the (pro)renin receptor. 2040 87

We present a critical review on emerging concepts on the role of (pro)renin receptor, (P)RR, in diabetic and hypertensive nephropathy. Discovery of nonproteolytic activation of prorenin by the receptor led to nontoxic peptidic prorenin receptor blocker. The receptor blocker permitted long-term in vivo studies on the role of (P)RR in diabetic and hypertensive end-organ damage. Chronic infusion of receptor blocker prevented streptozotocin diabetic nephropathy and attenuated hypertensive cardiomyopathy and nephropathy. In support of these results, transgenic rats overexpressing the receptor nonselectively developed renal glomerulopathy with aging without elevating blood glucose or blood pressures. It indicated that the receptor overexpression alone is sufficient for end-organ damage, and diabetes mellitus and hypertension induce the end-organ damage by increasing (P)RR expression. We propose that (P)RR is a pivotal link between pathogenesis of diabetes mellitus and end-organ damage. (P)RR seems to activate this mechanism largely by activating receptor signals rather than by local angiotensin II. We realized that (P)RR blocker is a competitive inhibitor against prorenin, and its efficiency depends on ambient concentration of prorenin and renin. Optimization of the condition will be necessary to maximize the inhibitory and therapeutic effects.
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PMID:Renin/prorenin receptor, (P)RR, in end-organ damage: current issues in 2007. 2040 4

Previous studies have demonstrated that prorenin plays a significant role in the development and progression of nephropathy in streptozotocin-induced diabetic animals, a model for type 1 diabetes, through a (pro)renin receptor-dependent mechanism. However, whether this novel mechanism also contributes to the mechanism of diabetic nephropathy in type 2 diabetes has remained undetermined. In 16-week-old db/db mice, a model for type 2 diabetes, we found a significant degree of glomerulosclerosis, enhanced immunostaining for the active site of renin (representing non-proteolytically activated prorenin), and an increased immunoreactivity to activated extracellular-signal-related protein kinase 1/2 in the kidneys. These changes were blocked by the chronic subcutaneous administration (1 mg/kg/day) of a decoy peptide with the "handle region" structure, which competitively inhibits prorenin binding to a "handle region"-specific binding protein, such as the (pro)renin receptor. The kidneys of db/db mice also contained increased angiotensin (Ang) I and II levels, eliciting significant microalbuminuria. Treatment with the "handle region" peptide significantly decreased the renal content of Ang I and II and inhibited the development of microalbuminuria. Thus prorenin also contributes to the development of nephropathy in type II diabetes, probably through a (pro)renin receptor-dependent mechanism.
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PMID:Involvement of receptor-bound prorenin in development of nephropathy in diabetic db/db mice. 2040 15

Hypertension, a serious disease affecting almost a billion people (25% of adults) worldwide, is a major modifiable risk factor for cardiovascular (CV) and renal disease. Despite numerous advances in the pharmacologic treatment of high blood pressure (BP) and availability of several antihypertensive drugs to treat hypertension, a significant proportion of treated hypertensive patients still have uncontrolled high BP, and thus, face serious morbidity and mortality. Furthermore, it is not sufficient to aim for optimum BP control, but to treat all CV risk factors, protect end-organ damage, prevent progression of disease, and prevent long-range adverse effects of the drugs. Therefore, new therapeutic modalities have to be developed to achieve the above objectives. Some years ago, investigators identified renin inhibition as the preferred pharmacologic approach to blockade of the renin-angiotensin system. Renin is a monospecific enzyme that catalyzes the rate-limiting step in the synthesis of angiotensin II. Amplified enzymatic activity and additional physiologic effects occur when renin and prorenin bind to the (pro)renin receptor. Until very recently, development of clinically effective renin inhibitors remained elusive but molecular modeling was used to develop aliskiren and other renin inhibitors that produce sustained suppression of plasma renin activity after oral administration with a dose-dependent BP. Additional studies will ultimately determine the place of renin inhibition in the treatment of hypertension and related CV disorders.
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PMID:Direct renin inhibitors as antihypertensive agents. 2047 79

The (pro)renin receptor is a protein that binds prorenin and renin in tissues, leading to their activation and, at the same time, to the initiation of intracellular signaling. The activation of local renin-angiotensin systems may play an important role in tissue damage induced by cardiovascular diseases and diabetes. However, (pro)renin receptor is also called ATP6ap2 because it has been shown to be associated with vacuolar H(+)-ATPase involvement in vesicular acidification and signaling in cells. Notably, lack of the protein in vertebrates leads to developmental alterations and early embryonic lethality probably as a result of the recently discovered role of the (pro)renin receptor and the vacuolar H(+)-ATPase in Wnt signaling. This review summarizes the current findings about these two functions of (pro)renin receptor/ATP6ap2 pointing out the possible links between both.
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PMID:Physiology of the (pro)renin receptor: Wnt of change? 2050 55

Prorenin, the inactive precursor of renin has been suggested to be an indicator of diabetic complications including retinopathy. This concept was originally based on findings that prorenin is elevated in the plasma and vitreous of patients with diabetic retinopathy. Experimental studies in animal models of diabetic retinopathy and retinopathy of prematurity, have confirmed these reports and localized prorenin to macroglial Muller cells and blood vessels. The identification of a (pro)renin receptor ((P)RR) which binds both prorenin and renin, and influences intracellular signaling pathways independently of angiotensin II, suggests that prorenin-(P)RR may be pathogenic under certain circumstances. Given recent evidence from clinical trials that angiotensin II blockade improves to some extent retinopathy in diabetic patients, the development of (P)RR antagonists could have promise as an adjunct treatment for retinal diseases where prorenin is up-regulated. This review will discuss the cellular location of the renin-angiotensin system in the retina, evidence that angiotensin II blockade is beneficial for both retinal vascular, neuronal and glial pathology and place this information in the context of the development of (P)RR inhibitors.
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PMID:Prorenin and the (pro)renin receptor: do they have a pathogenic role in the retina? 2051 75

Recently we showed that fructose feeding in rats induced nonproteolytic activation of prorenin and subsequent angiotensin II production in skeletal muscle. In addition, a pharmacological inhibitor of prorenin/(pro)renin receptor interaction attenuated the development of insulin resistance. However, the inhibitor did not ameliorate the glucose intolerance in transgenic rats overexpressing the human renin gene. This review article summarizes the current knowledge of the effects of the prorenin/(pro)renin receptor system on insulin resistance and its potential as a therapeutic target.
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PMID:Prorenin/renin and insulin resistance. 2051 85

Due to its pivotal role in blood pressure control and renal pathologies there is renewed interest in renin and its precursor prorenin. Also, the newly discovered (pro)renin receptor is a new element of the ever broadening renin-angiotensin system (RAS). The complexity of RAS including the recently recognized collecting duct site of (pro)renin (a term denoting both renin and prorenin) synthesis requires the use of advanced research techniques such as multiphoton fluorescence microscopy. With the help of this technology we have pioneered an imaging approach to directly visualize (pro)renin content, release and tissue activity in the living kidney. The use of this technology is reviewed here and exemplified by the direct visualization of (pro)renin activity in the collecting duct. New pharmacological tools, the renin inhibitor aliskiren and the handle region peptide (decoy peptide) was used to further characterize the intra-renal, collecting duct RAS.
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PMID:Recent advances in tissue (pro)renin imaging. 2051 94


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