Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The (pro)renin receptor [(P)RR] is a single trans-membrane domain receptor that mediates renin and prorenin specific effects. The receptor 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 cascade leading to cell proliferation and to up-regulation of profibrotic genes expression. Studies in genetically modified animals over-expressing (P)RR suggest a direct role for (P)RR cardiovascular and renal pathologies since rats over-expressing (P)RR in vascular smooth-muscle cells develop high blood pressure and those with an ubiquitous over-expression of (P)RR have glomerulosclerosis and proteinuria. A peptide called "handle region peptide" (HRP) mimicking part of the prosegment of prorenin was claimed to block prorenin binding to (P)RR and its activation. The mechanism of action of HRP and its specificity for (P)RR remains very controversial although infusion of this peptide gave spectacular results by preventing diabetic nephropathy in angiotensin II type1a receptor-deficient mice. In contrast to the other components of the renin angiotensin system, (P)RR is necessary to cell survival and proliferation and a mutation of (P)RR is associated with mental retardation and epilepsy, pointing to an essential role of (P)RR in brain development. The (pro)renin receptor is a more complex protein than anticipated and in depth studies of its functions that are likely not restricted to the renin angiotensin system are needed especially in the perspective of the design of a (P)RR blocker.
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PMID:Physiology and pharmacology of the (pro)renin receptor. 1824 93

The discovery of a (pro)renin receptor ((P)RR) and the introduction of renin inhibitors in the clinic has brought prorenin, the inactive proenzyme form of renin, back into the spotlight. The (P)RR binds both renin and its inactive precursor prorenin, and their binding triggers intracellular signaling that up-regulates the expression of profibrotic genes. Furthermore, binding of prorenin unmasks its active site and endows prorenin with angiotensin I-generating activity. Many studies have attempted to establish a link between (P)RR and hypertension, (P)RR and tissue fibrosis associated with hypertension and with diabetic nephropathy. Models of transgenic rats overexpressing (P)RR develop high blood pressure and have glomerulosclerosis, suggesting a link between increased (P)RR and these pathologies, but no definite proof of any role of (P)RR in other models of cardiovascular or renal diseases could be established because of the absence of any specific (P)RR antagonist and of tissue-specific (P)RR null mice. Nevertheless, a study in a large cohort of Japanese men has shown a correlation between a polymorphism in the (P)RR gene and increased ambulatory blood pressure. Finally, a mutation in the (P)RR gene is responsible for mental retardation and epilepsy, indicating that (P)RR is essential during brain development.
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PMID:Potential role of the (pro)renin receptor in cardiovascular and kidney diseases. 2038 69

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