Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 (pro)renin receptor [(P)RR] plays a pivotal role in the renin-angiotensin system. Experimental models emphasize the role of (P)RR in organ damage associated with hypertension and diabetes. However, a mutation of the (P)RR gene, resulting in frame deletion of exon 4 [Delta4-(P)RR] is associated with X-linked mental retardation (XLMR) and epilepsy pointing to a novel role of (P)RR in brain development and cognitive function. We have studied (P)RR expression in mouse brain, as well as the effect of transfection of Delta4-(P)RR on neuronal differentiation of rat neuroendocrine PC-12 cells induced by nerve growth factor (NGF). In situ hybridization showed a wide distribution of (P)RR, including in key regions involved in the regulation of blood pressure and body fluid homeostasis. In mouse neurons, the receptor is on the plasma membrane and in synaptic vesicles, and stimulation by renin provokes ERK1/2 phosphorylation. In PC-12 cells, (P)RR localized mainly in the Golgi and in endoplasmic reticulum and redistributed to neurite projections during NGF-induced differentiation. In contrast, Delta4-(P)RR remained cytosolic and inhibited NGF-induced neuronal differentiation and ERK1/2 activation. Cotransfection of PC-12 cells with (P)RR and Delta4-(P)RR cDNA resulted in altered localization of (P)RR and inhibited (P)RR redistribution to neurite projections upon NGF stimulation. Furthermore, (P)RR dimerized with itself and with Delta4-(P)RR, suggesting that the XLMR and epilepsy phenotype resulted from a dominant-negative effect of Delta4-(P)RR, which coexists with normal transcript in affected males. In conclusion, our results show that (P)RR is expressed in mouse brain and suggest that the XLMR and epilepsy phenotype might result from a dominant-negative effect of the Delta4-(P)RR protein.
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PMID:A role of the (pro)renin receptor in neuronal cell differentiation. 1949 75

The incidence of chronic kidney disease, such as diabetic nephropathy, is increasing throughout the world. Many biologically active peptides play important roles in the kidney. The classical example is the renin-angiotensin system (RAS). Angiotensin II plays critical roles in the progression of chronic kidney disease through its vasoconstrictor action, stimulatory action on cell proliferation, and reactive oxygen-generating activity. A renin inhibitor, aliskiren, has recently been shown to be a clinically effective drug to reduce proteinuria in patients with diabetic nephropathy. (Pro)renin receptor, a specific receptor for renin and prorenin, was newly identified as a member of the RAS. When bound to prorenin, (pro)renin receptor activates the angiotensin I-generating activity of prorenin in the absence of cleavage of the prosegment, and directly stimulates the pathway of mitogen-activated protein kinase independently from the RAS. The kidney peptides that antagonize the intrarenal RAS may have renoprotective actions. Adrenomedullins, potent vasodilator peptides, have been shown to have renoprotective actions. On the other hand, urotensin II, a potent vasoconstrictor peptide, may promote the renal dysfunction in chronic kidney disease together with the renal RAS. Thus, in addition to the renin inhibitor and (pro)renin receptor, adrenomedullins and urotensin II may be novel targets to develop therapeutic strategies against chronic kidney disease.
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PMID:The renin-angiotensin system, adrenomedullins and urotensin II in the kidney: possible renoprotection via the kidney peptide systems. 1947 9

The (pro)renin receptor ([P]RR) is a transmembrane protein that binds both renin and prorenin with high affinity, increasing the catalytic cleavage of angiotensinogen and signaling intracellularly through mitogen-activated protein kinase activation. Although initially reported as having no homology with any known membrane protein, other studies have suggested that the (P)RR is an accessory protein, named ATP6ap2, that associates with the vacuolar H(+)-ATPase, a key mediator of final urinary acidification. Using in situ hybridization, immunohistochemistry, and electron microscopy, together with serial sections stained with nephron segment-specific markers, we found that (P)RR mRNA and protein were predominantly expressed in collecting ducts and in the distal nephron. Within collecting ducts, the (P)RR was most abundant in microvilli at the apical surface of A-type intercalated cells. Dual-staining immunofluorescence demonstrated colocalization of the (P)RR with the B1/2 subunit of the vacuolar H(+)-ATPase, the ion exchanger that secretes H(+) ions into the urinary space and that associates with an accessory subunit homologous to the (P)RR. In collecting duct/distal tubule lineage Madin-Darby canine kidney cells, extracellular signal-regulated kinase 1/2 phosphorylation, induced by either renin or prorenin, was attenuated by the selective vacuolar H(+)-ATPase inhibitor bafilomycin. The predominant expression of the (P)RR at the apex of acid-secreting cells in the collecting duct, along with its colocalization and homology with an accessory protein of the vacuolar H(+)-ATPase, suggests that the (P)RR may function primarily in distal nephron H(+) transport, recently noted to be, at least in part, an angiotensin II-dependent phenomenon.
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PMID:The (Pro)renin receptor: site-specific and functional linkage to the vacuolar H+-ATPase in the kidney. 1954 73

(Pro)renin receptor (PRR) is present in renal glomeruli, and its expression is up-regulated in diabetes. Similarly, renal inflammation is increased in the presence of hyperglycemia. The linkage between PRR and renal inflammation is not well established. We hypothesized that glucose-induced up-regulation of PRR leads to increased production of the proinflammatory factors IL-1beta and cyclooxygenase-2 (COX-2). Studies were conducted in rat mesangial cells (RMCs) exposed to 30 mm D-glucose for 2 wk followed by PRR small interfering RNA knockdown, IL-1 receptor blockade with IL-1 receptor antagonist or angiotensin II type 1 receptor blockade with valsartan. The results showed that D-glucose treatment up-regulates prorenin, renin, angiotensin II, PRR, IL-1beta, and COX-2 mRNA and protein expression and increases phosphorylation of ERK1/2, c-Jun N-terminal kinase, c-Jun, and nuclear factor-kappaB (NF-kappaB) p65 (serine 276,468 and 536), respectively. PRR small interfering RNA attenuated PRR, IL-1beta, and COX-2 mRNA and protein expressions and significantly decreased angiotensin II production and phosphorylation of ERK1/2 and NF-kappaB p65 associated with high glucose exposure. Similarly, IL-1 receptor antagonist significantly reduced COX-2 mRNA and protein expression induced by high glucose. COX-2 inhibition reduced high-glucose-induced PRR expression. We conclude that glucose induces the up-regulation of PRR and its ligands prorenin and renin, leading to increased IL-1beta and COX-2 production via the angiotensin II-dependent pathway. It is also possible that PRR could enhance the production of these inflammatory cytokines through direct stimulation of ERK1/2-NF-kappaB signaling cascade.
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PMID:Glucose promotes the production of interleukine-1beta and cyclooxygenase-2 in mesangial cells via enhanced (Pro)renin receptor expression. 1986 3

The (pro)renin receptor (PRR) binds renin and prorenin, its proenzyme inactive form. Receptor-bound prorenin becomes enzymatically active and binding then activates the MAP kinases ERK1/2 and p38 pathways, leading to upregulation of profibrotic and cyclooxygenase-2 genes independent of angiotensin II generation. These characteristics explain the interest in the potential role of PRR in organ damage in diseases associated with activation of the renin-angiotensin system (RAS), in particular hypertension and diabetes. Although identification of PRR has improved our understanding of the physiology of the tissue RAS, its role in pathology is far from clear. Transgenic animals overexpressing PRR ubiquitously or selectively in smooth-muscle cells develop high BP or glomerulosclerosis, and increased expression of PRR is reported in models of hypertension or kidney damage. However, definitive proof is still lacking for a role for PRR in disease, or by showing improvement of disease by tissue-specific ablation of PRR or by administration of a specific PRR antagonist. Furthermore, the early embryonic lethality seen in PRR-null mice suggests PRR has additional essential cellular functions we do not understand.
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PMID:The biology of the (pro)renin receptor. 1991 80

The renin-angiotensin system (RAS) is one of the most important systems in physiology and in pathology. The (pro)renin receptor ((P)RR) is a new component of the system that has attracted much attention being potentially a new therapeutic target. The receptor binds renin and the inactive proenzyme form of renin, prorenin, and the binding triggers the activation of the mitogen-activated protein kinase p42/p44 followed by up-regulation of the expression of profibrotic genes. In addition, prorenin bound to (P)RR undergoes a conformational change and becomes catalytically active. Many animal studies have tried to demonstrate a role for (P)RR in hypertension and in tissue damage associated with diabetes, but if they showed that increased (P)RR was found in kidney of diabetic mice associated with glomerulosclerosis and in heart of hypertensive rats associated with cardiac fibrosis, no definite link could be established between elevated (P)RR and cardiovascular and renal pathologies because of the absence of animal models with a tissue-specific (P)RR knock-out and a lack of a (P)RR antagonist. On the contrary, the human and the animal mutations are calling our attention to an essential role of (P)RR during early development, in particular in neuronal development.
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PMID:The (pro)renin receptor in health and disease. 2010 54

The renin-angiotensin system (RAS) is one of the most important systems in physiology and in pathology. The (pro)renin receptor [(P)RR] is a new component of the system that has attracted much attention, being potentially a new therapeutic target, because the binding of renin and of prorenin triggers the activation of the mitogen-activated protein kinase p42/p44 followed by up-regulation of the expression of profibrotic genes. and because prorenin bound to (P)RR becomes catalytically active. The introduction of a renin inhibitor in the treatment of hypertension and of organ damages, together with the discovery of (P)RR, has revived the interest for the RAS and for potential new RAS blockers, in order to optimize RAS blockade in tissues.
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PMID:[The prorenin receptor]. 2012 88

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


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