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)

Renin is an aspartyl protease essential for the control of blood pressure and was long suspected to have cellular receptors. We report the expression cloning of the human renin receptor complementary DNA encoding a 350-amino acid protein with a single transmembrane domain and no homology with any known membrane protein. Transfected cells stably expressing the receptor showed renin- and prorenin-specific binding. The binding of renin induced a fourfold increase of the catalytic efficiency of angiotensinogen conversion to angiotensin I and induced an intracellular signal with phosphorylation of serine and tyrosine residues associated to an activation of MAP kinases ERK1 and ERK2. High levels of the receptor mRNA are detected in the heart, brain, placenta, and lower levels in the kidney and liver. By confocal microscopy the receptor is localized in the mesangium of glomeruli and in the subendothelium of coronary and kidney artery, associated to smooth muscle cells and colocalized with renin. The renin receptor is the first described for an aspartyl protease. This discovery emphasizes the role of the cell surface in angiotensin II generation and opens new perspectives on the tissue renin-angiotensin system and on renin effects independent of angiotensin II.
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PMID:Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. 1269 59

The role of proteases and of antiproteases in the progression of renal disease is well established. Most studies have focused on the serine-proteases of the plasmin/plasminogen activator system and on matrix metalloproteases. Recently, renin, an aspartyl-protease, has attracted much attention because of the role of angiotensin II in the progression of renal lesions and because of the discovery of a functional renin receptor. This receptor is a 45 kDa membrane-protein that binds specifically renin and prorenin. The binding of renin induces an increase of the catalytic efficiency of angiotensinogen conversion into angiotensin I by receptor-bound renin compared to renin in soluble phase, and a rapid phosphorylation of the receptor on serine and tyrosine residues associated with an activation of MAP kinases ERK1/2. Immunofluorescence and confocal analyses on normal human kidney and cardiac biopsies show that the receptor is localized within the mesangial area of glomeruli and in the sub-endothelium of kidney and coronary arteries, associated to smooth-muscle cells. In summary, this receptor exerts dual effects, mediating renin cellular response and increasing the efficiency of angiotensinogen cleavage by membrane-bound renin. These observations emphasizes the importance of angiotensin II generation at the cell surface and the cellular effects of renin add new dimensions (and complexity) to the classical dogma that angiotensin II is the only effector of the RAS.
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PMID:[Proteases and antiproteases in the progression of chronic renal insufficiency lesions. The role of the tissue renin-angiotensin system and the renin receptor]. 1264 96

Our model of the renin-angiotensin system has become increasingly complex with the identification of new components and additional roles for angiotensin peptides and their receptors. A functional (pro)renin receptor has been cloned. It acts as (pro)renin co-factor on the cell surface, enhancing the efficiency of angiotensinogen cleavage by (pro)renin and unmasking prorenin catalytic activity. Binding of (pro)renin to the receptor mediates (pro)renin cellular effects by activating MAP kinases ERK1/2. Immunofluorescence studies have located the receptor on mesangial and vascular smooth-muscle cells in human heart and kidney. This suggests that the renin receptor may represent a mean of capturing (pro)renin from the circulation and concentrating it at the interface between smooth-muscle and endothelial cells. This recent discovery of a functional (pro)renin receptor forces the emergence of a new concept that casts renin as potentially playing a direct role in tissue damage, especially in situations where the tissue RAS is activated.
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PMID:[The (pro)renin receptor: biology and functional significance]. 1558 81

The renin-angiotensin system (RAS) is essential for blood pressure control and water-electrolyte balance. Until the discovery of the renin receptor, renin was believed to be mainly a circulating enzyme with a unique function, the cleavage of angiotensinogen. We report a unique mutation in the renin receptor gene (ATP6AP2) present in patients with X-linked mental retardation and epilepsy (OMIM no. 300423), but absent in 1200 control X-chromosomes. A silent mutation (c.321C>T, p.D107D) residing in a putative exonic splicing enhancer site resulted in inefficient inclusion of exon 4 in 50% of renin receptor mRNA, as demonstrated by quantitative RT-PCR. Analysis of membrane associated-receptor molecular forms showed the presence of full-length and truncated proteins in the patient. Functional analysis demonstrated that the mutated receptor could bind renin and increase renin catalytic activity, similar to the wild-type receptor, but resulted in a modest and reproducible impairment of ERK1/2 activation. Thus, our findings confirm the importance of the RAS in cognitive processes and indicate a novel specific role for the renin receptor in cognitive functions and brain development.
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PMID:A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor. 1574 49

Tissue accumulation of circulating prorenin results in angiotensin generation, but could also, through binding to the recently cloned (pro)renin receptor, lead to angiotensin-independent effects, like p42/p44 mitogen-activated protein kinase (MAPK) activation and plasminogen-activator inhibitor (PAI)-1 release. Here we investigated whether prorenin exerts angiotensin-independent effects in neonatal rat cardiomyocytes. Polyclonal antibodies detected the (pro)renin receptor in these cells. Prorenin affected neither p42/p44 MAPK nor PAI-1. PAI-1 release did occur during coincubation with angiotensinogen, suggesting that this effect is angiotensin mediated. Prorenin concentration-dependently activated p38 MAPK and simultaneously phosphorylated HSP27. The latter phosphorylation was blocked by the p38 MAPK inhibitor SB203580. Rat microarray gene (n=4800) transcription profiling of myocytes stimulated with prorenin detected 260 regulated genes (P<0.001 versus control), among which genes downstream of p38 MAPK and HSP27 involved in actin filament dynamics and (cis-)regulated genes confined in blood pressure and diabetes QTL regions, like Syntaxin-7, were overrepresented. Quantitative real-time RT-PCR of 7 selected genes (Opg, Timp1, Best5, Hsp27, pro-Anp, Col3a1, and Hk2) revealed temporal regulation, with peak levels occurring after 4 hours of prorenin exposure. This regulation was not altered in the presence of the renin inhibitor aliskiren or the angiotensin II type 1 receptor antagonist eprosartan. Finally, pilot 2D proteomic differential display experiments revealed actin cytoskeleton changes in cardiomyocytes after 48 hours of prorenin stimulation. In conclusion, prorenin exerts angiotensin-independent effects in cardiomyocytes. Prorenin-induced stimulation of the p38 MAPK/HSP27 pathway, resulting in alterations in actin filament dynamics, may underlie the severe cardiac hypertrophy that has been described previously in rats with hepatic prorenin overexpression.
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PMID:Prorenin induces intracellular signaling in cardiomyocytes independently of angiotensin II. 1694 Feb 9

Recent evidence indicates that renin itself might be profibrotic, independent of angiotensin II; however, the signaling system by which renin exerts a direct effect is not known. We tested the hypothesis that renin receptor activation, in turn, activates the extracellular-signal regulated kinase 1 and 2 (ERK1/2) of the mitogen-activated protein kinase system in mesangial cells. Recombinant rat renin induced a rapid phosphorylation of ERK1/2 and subsequent cell proliferation in a dose- and time-dependent manner. ERK1/2 activation by renin addition was not altered by angiotensin-converting enzyme inhibition or angiotensin receptor blockade. An ERK kinase inhibitor significantly reduced the renin-induced ERK1/2 phosphorylation and the subsequent increase in transforming growth factor-beta1 (TGF-beta1) and plasminogen activator inhibitor-1 mRNA expression. A small-inhibiting RNA, siRNA, against the renin receptor completely blocked ERK1/2 activation by rat renin. We conclude that renin induces ERK1/2 activation though a receptor-mediated, angiotensin II-independent mechanism in mesangial cells. This renin-activated pathway triggers cell proliferation along with TGF-beta1 and plasminogen activator inhibitor-1 gene expression. This system may play an important role in the overall profibrotic actions of renin.
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PMID:Renin-stimulated TGF-beta1 expression is regulated by a mitogen-activated protein kinase in mesangial cells. 1739 11

The (pro)renin receptor [(P)RR], a new component the renin-angiotensin system, was cloned recently. The (P)RR promotes direct mitogen-activated protein kinase signaling and nonproteolytic prorenin activation. We investigated the role of a (P)RR blocker, a peptide consisting of 10 amino acids from the prorenin prosegment called the "handle-region" peptide (HRP), on target organ damage in renovascular hypertensive 2-kidney, 1-clip (2K1C) rats. Vehicle-treated 2K1C rats were compared with HRP-treated 2K1C rats (3.5 mug/kg per day) and sham-operated controls. Vehicle-treated 2K1C rats developed hypertension (186+/-17 mm Hg), cardiac hypertrophy (3.16+/-0.16 mg/g), renal inflammation, fibrosis, vascular, and tubular damage. Chronic HRP treatment did not affect blood pressure (194+/-15 mm Hg), cardiac hypertrophy (2.97+/-0.11 mg/g), or renal damage. Furthermore, we investigated the renal renin and (P)RR expression. The clipped kidney of 2K1C and HRP-treated 2K1C rats showed a higher renin expression and juxtaglomerular index compared with sham-operated kidneys. The unclipped kidney showed suppressed renin expression. In contrast, (P)RR mRNA expression was not altered in any group. Plasma renin activity and aldosterone were increased in 2K1C rats compared with sham controls. HRP-treated 2K1C rats tended to lower plasma renin activity but showed similar aldosterone levels as vehicle-treated 2K1C rats. Our results indicate that blockade of the (P)RR with HRP does not improve target organ damage in renovascular hypertensive rats.
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PMID:(Pro)renin receptor peptide inhibitor "handle-region" peptide does not affect hypertensive nephrosclerosis in Goldblatt rats. 1821 68

The recently cloned (pro)renin receptor [(P)RR] mediates renin-stimulated cellular effects by activating mitogen-activated protein kinases and promotes nonproteolytic prorenin activation. In vivo, (P)RR is said to be blocked with a peptide consisting of 10 amino acids from the prorenin prosegment called the "handle-region" peptide (HRP). We tested whether human prorenin and renin induce extracellular signal-regulated kinase (ERK) 1/2 activation and whether the direct renin inhibitor aliskiren or the HRP inhibits the receptor. We detected the (P)RR mRNA and protein in isolated human monocytes and in U937 monocytes. In U937 cells, we found that both human renin and prorenin induced a long-lasting ERK 1/2 phosphorylation despite angiotensin II type 1 and 2 receptor blockade. In contrast to angiotensin II-ERK signaling, renin and prorenin signaling did not involve the epidermal growth factor receptor. A mitogen-activated protein kinase kinase 1/2 inhibitor inhibited both renin and prorenin-induced ERK 1/2 phosphorylation. Neither aliskiren nor HRP inhibited binding of (125)I-renin or (125)I-prorenin to (P)RR. Aliskiren did not inhibit renin and prorenin-induced ERK 1/2 phosphorylation and kinase activity. Fluorescence-activated cell sorter analysis showed that, although fluorescein isothiocyanate-labeled HRP bound to U937 cells, HRP did not inhibit renin or prorenin-induced ERK 1/2 activation. In conclusion, prorenin and renin-induced ERK 1/2 activation are independent of angiotensin II. The signal transduction is different from that evoked by angiotensin II. Aliskiren has no (P)RR blocking effect and did not inhibit ERK 1/2 phosphorylation or kinase activity. Finally, we found no evidence that HRP affects renin or prorenin binding and signaling.
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PMID:Prorenin and renin-induced extracellular signal-regulated kinase 1/2 activation in monocytes is not blocked by aliskiren or the handle-region peptide. 1821 69

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

(Pro)renin receptor (PRR), the newest member of the renin-angiotensin system (RAS), is turning out to be an important player in the regulation of the cardiovascular system. It plays a pivotal role in activation of the local RAS and stimulates signalling pathways involved in proliferative and hypertrophic mechanisms. However, the role of PRR in the brain remains unknown. Thus, our objective in this study was to determine whether a functional PRR is present in neurons within the brain. Neuronal co-cultures from the hypothalamus and brainstem areas of neonatal rat brain express PRR mRNA. Immunoreactivity for PRR was primarily localized on the neuronal cell soma and in discrete areas in the neurites. Treatment of neurons with renin, in the presence of 2 microm losartan, caused a time- and dose-dependent stimulation of phosphorylation of extracellular signal related kinase ERK1 (p44) and ERK2 (p42) isoforms of mitogen-activated protein kinase. Optimal stimulation of fourfold was observed within 2 min with 20 nm renin. Electrophysiological recordings showed that treatment of the neurons with renin, in the presence of 2 microm losartan, resulted in a steady and stable decrease in action potential frequency. A 46% decrease in action potential frequency was observed within 5 min of treatment and was attenuated by co-incubation with a PRR blocking peptide. These observations demonstrate that the PRR is present in neurons within the brain and that its activation by renin initiates the MAP kinase signalling pathway and inhibition of neuronal activity.
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PMID:Characterization of a functional (pro)renin receptor in rat brain neurons. 1832 51


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