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)

The (pro)renin receptor ((P)RR) is a unique molecule that binds prorenin and renin in tissues, not only leading to their activation, but also inducing intracellular signaling. As a key player in the local renin-angiotensin system, (P)RR activation plays an important role in the development of cardiac fibrosis and proteinuria in hypertension and diabetes. Intriguingly, the fragment (P)RR is also called ATP6AP2 because it has been shown to be associated with vacuolar-type H(+)-ATPase (V-ATPase). The V-ATPase is a multi-subunit proton pump involved in diverse and fundamental cellular processes, including receptor-mediated endocytosis, processing of proteins and signaling molecules, membrane sorting and trafficking, and activation of lysosomal enzymes. The role of (P)RR in the function of the V-ATPase is implicated in the previous findings and vigorously investigated in the recent studies. Furthermore, the novel function of the (P)RR as an adaptor protein between the Wnt receptor complex and the V-ATPase was discovered. Thus, the (P)RR is a multi-functional molecule that shows the complex structure and behaviour. This review highlights the current insights and the future perspectives in research regarding the (P)RR and mammalian V-ATPase.
 ...
PMID:Functional characterization of (pro)renin receptor in association with V-ATPase. 2162 30

The discovery of a (pro)renin receptor ((P)RR) in 2002 provided a long-sought explanation for tissue renin-angiotensin system (RAS) activity and a function for circulating prorenin, the inactive precursor of renin, in end-organ damage. Binding of renin and prorenin (referred to as (pro)renin) to the (P)RR increases angiotensin I formation and induces intracellular signalling, resulting in the production of profibrotic factors. However, the (pro)renin concentrations required for intracellular signalling in vitro are several orders of magnitude above (patho)physiological plasma levels. Moreover, the phenotype of prorenin-overexpressing animals could be completely attributed to angiotensin generation, possibly even without the need for a receptor. The efficacy of the only available putative (pro)renin receptor blocker handle region peptide remains doubtful, leading to inconclusive results. The fact that, in contrast to other RAS components, (P)RR knock-outs, even tissue-specific, are lethal, points to an important, (pro)renin-independent, function of the (P)RR. Indeed, recent research has highlighted ancillary functions of the (P)RR as an essential accessory protein of the vacuolar-type H(+)-ATPase (V-ATPase), and in this role, it acts as an intermediate in Wnt signalling independent of (pro)renin. In conclusion, (pro)renin-dependent signalling is unlikely in non-(pro)renin synthesizing organs, and the (P)RR role in V-ATPase integrity and Wnt signalling may explain some, if not all of the phenotypes previously associated with (pro)renin-(P)RR interaction.
 ...
PMID:The (pro)renin receptor. A decade of research: what have we learned? 2254 58

Biologically active peptides are widely expressed throughout in human bodies. For example, endothelin-1 and adrenomedullin are expressed in almost all types of cells, including neurons, glial cells, fibroblasts, macrophages, cardiomyocytes, vascular endothelial cells, epithelial cells and cancer cells of various origins. Expression of both these peptides is induced by stimuli, such as hypoxia and inflammatory cytokines. They have a variety of biological functions, such as effects on brain function, hormone secretion, the cardiovascular system and cell proliferation. By contrast, orexins (hypocretins) and melanin-concentrating hormone (MCH) are specifically expressed in the hypothalamus, particularly in the lateral hypothalamus, although very low concentrations of these peptides are found in the peripheral tissues. Orexins and MCH play coordinated, but distinct physiological roles in the regulation of sleep-wake cycle, appetite, emotion and other brain functions. The cardiovascular system is regulated by cardiovascular peptides, such as natriuretic peptides, endothelins and angiotensin II. The renin-angiotensin system (RAS) is one of the most classical regulatory systems on blood pressure, electrolytes and kidney. (Pro)renin receptor is a novel member of the RAS and may be related to the pathophysiology of microvascular complications of hypertension and diabetes mellitus. Moreover, (pro)renin receptor forms a functional complex with vacuolar-type H(+)-ATPase, which plays an important physiological role in maintaining the acidic environment of intracellular compartments including secretory vesicles. Perhaps, the complex of (pro)renin receptor and vacuolar-type H(+)-ATPase may be important for the post-translational processing and secretion of many biologically active peptides.
...
PMID:Ubiquitous expression and multiple functions of biologically active peptides. 2586 73

Tissue angiotensin generation depends on the uptake of circulating (kidney-derived) renin and/or its precursor prorenin (together denoted as (pro)renin). Since tissue renin levels are usually higher than expected based upon the amount of (renin-containing) blood in tissue, an active uptake mechanism has been proposed. The (pro)renin receptor ((P)RR), discovered in 2002, appeared a promising candidate, although its nanomolar affinity for renin/prorenin is many orders of magnitude above their levels in blood. This review discusses (P)RR-related research since its discovery. First, encouraging in vitro findings supported detrimental effects of (pro)renin-(P)RR interaction, even resulting in angiotensin-independent signaling. Moreover, the putative (P)RR blocker "handle region peptide" (HRP) yielded beneficial effects in various cardiovascular animal models. Then doubt arose whether such interaction truly occurs in vivo, and (P)RR deletion unexpectedly turned out to be lethal. Moreover, HRP results could not be confirmed. Finally, it was discovered that the (P)RR actually is a component of vacuolar-type H(+)-ATPase, a multisubunit protein found in virtually every cell type which is essential for vesicle trafficking, protein degradation, and coupled transport. Nevertheless, selective (P)RR blockade in the brain with the putative antagonist PRO20 (corresponding with the first 20 amino acids of prorenin's prosegment) reduced blood pressure in the deoxycorticosteroneacetate (DOCA)-salt model, and (P)RR gene single nucleotide polymorphisms associate with hypertension. To what degree this relates to (pro)renin remains uncertain. The concept of (P)RR blockade in hypertension, if pursued, requires rigorous testing of any newly designed antagonist, and may not hold promise given the early death of tissue-specific (P)RR knockout animals.
...
PMID:The Role of the (Pro)renin Receptor in Hypertensive Disease. 2589 Aug 29