Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Literature suggests the involvement of the renin-angiotensin system and transforming growth factor (TGF)-beta in the renal injury that follows chronic ureteric obstruction. SMAD proteins and the JNK1 cascade are essential components of TGF-beta signaling machinery, and recent data suggest cooperative interaction between JNK1 and SMAD proteins in TGF-beta-mediated gene expression. We used a rat model of chronic unilateral ureteric obstruction to study the effects of candesartan, an AT(1A)-receptor blocker, on tissue morphology and the activities of JNK1 and SMAD2 protein in the kidney. Ureteric obstruction for 28 days leads to interstitial fibrosis, tubule atrophy, and marked activation of SMAD2 and JNK1, without significant change in p38 kinase or ERK. Candesartan treatment, however, attenuated the chronic tubulointerstitial injury in obstructed kidneys and was associated with significant preservation of kidney tissue mass. Furthermore, treatment with candesartan diminished JNK1 activity and downregulated SMAD2 protein and activity in obstructed kidneys. In conclusion, obstructed kidneys showed chronic tubulointerstitial injury, which was associated with JNK1 and SMAD2 activation. The renoprotective effects afforded by AT(1A)-receptor blockade in obstructive uropathy are consistent with attenuation of JNK1- and SMAD2-mediated renal injury.
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PMID:AT1A-mediated activation of kidney JNK1 and SMAD2 in obstructive uropathy: preservation of kidney tissue mass using candesartan. 1512 50

The chronic treatment of rats with N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) biosynthesis, results in hypertension. This inhibition of NO production results in activation of the renin-angiotensin system, with increased activity of the carboxypeptidase angiotensin I-converting enzyme (ACE). Since chronic NO inhibition increases ACE activity, we hypothesized that this inhibition could also affect the activities of other peptidases involved in cardiovascular functions. To test this possibility, we examined the activities of aminopeptidase M (APM), dipeptidyl peptidase IV (DPP IV), metalloendopeptidase 24.15 (MEP 24.15) and neutral endopeptidase 24.11 (NEP 24.11) in rat brain, heart, kidney, liver, lung and thoracic aorta. Male Wistar rats were treated chronically with L-NAME (80mgkg(-1) per day) administered in the drinking water for 4 weeks and their organs then removed and processed for the determination of peptidase activities. Treatment with L-NAME did not significantly alter the activities of the four peptidases in brain, heart, kidney, liver and lung. In contrast, in aorta, the activity of APM was slightly but significantly reduced whereas those of DPP IV and MEP 24.15 were markedly enhanced; NEP 24.11 was not detected in this tissue. Immunoblotting for DPP IV and MEP 24.15 showed increased expression in aortic tissue. Neither L-NAME (1-100microM) nor the NO donors sodium nitroprusside and 3-morpholinosydnonimine (SIN-1; 1-100microM) had any consistent effect on the activity of recombinant MEP 24.15 or renal DPP IV. The importance of MEP 24.15 in peptide metabolism was confirmed in pentobartibal-anesthetized rats pretreated with the MEP 24.15 inhibitor N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA2), which significantly potentiated the hypotensive response to bradykinin. The altered peptidase activities seen in aorta may contribute to modulating vascular responses in this model of hypertension.
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PMID:Peptidase activities in rats treated chronically with N(omega)-nitro-L-arginine methyl ester (L-NAME). 1519 92

In the RAS (renin-angiotensin system), Ang I (angiotensin I) is cleaved by ACE (angiotensin-converting enzyme) to form Ang II (angiotensin II), which has effects on blood pressure, fluid and electrolyte homoeostasis. We have examined the kinetics of angiotensin peptide cleavage by full-length human ACE, the separate N- and C-domains of ACE, the homologue of ACE, ACE2, and NEP (neprilysin). The activity of the enzyme preparations was determined by active-site titrations using competitive tight-binding inhibitors and fluorogenic substrates. Ang I was effectively cleaved by NEP to Ang (1-7) (kcat/K(m) of 6.2x10(5) M(-1) x s(-1)), but was a poor substrate for ACE2 (kcat/K(m) of 3.3x10(4) M(-1) x s(-1)). Ang (1-9) was a better substrate for NEP than ACE (kcat/K(m) of 3.7x10(5) M(-1) x s(-1) compared with kcat/K(m) of 6.8x10(4) M(-1) x s(-1)). Ang II was cleaved efficiently by ACE2 to Ang (1-7) (kcat/K(m) of 2.2x10(6) M(-1) x s(-1)) and was cleaved by NEP (kcat/K(m) of 2.2x10(5) M(-1) x s(-1)) to several degradation products. In contrast with a previous report, Ang (1-7), like Ang I and Ang (1-9), was cleaved with a similar efficiency by both the N- and C-domains of ACE (kcat/K(m) of 3.6x10(5) M(-1) x s(-1) compared with kcat/K(m) of 3.3x10(5) M(-1) x s(-1)). The two active sites of ACE exhibited negative co-operativity when either Ang I or Ang (1-7) was the substrate. In addition, a range of ACE inhibitors failed to inhibit ACE2. These kinetic data highlight that the flux of peptides through the RAS is complex, with the levels of ACE, ACE2 and NEP dictating whether vasoconstriction or vasodilation will predominate.
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PMID:Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. 1528 75

Brain natriuretic peptide (BNP) was isolated originally from porcine brain extracts but was soon defined as a cardiac natriuretic hormone. Together with the highly homologous atrial natriuretic peptide, it forms a dual natriuretic peptide system of the heart. The main stimulus for proBNP synthesis and secretion from cardiac myocytes is myocyte stretch. On secretion, the propeptide is split into the biologically active BNP and the remaining part of the prohormone N-terminal proBNP (NT-proBNP). In heart failure increased wall stretch, neurohormonal activation and hypoxia stimulate BNP secretion. The recently demonstrated production of BNP by stimulated cardiac fibroblasts is of uncertain pathophysiologic importance. In contrast to atrial natriuretic peptide, BNP is a constitutively secreted hormone with relatively little intracellular storage of mature peptide. In the normal state, the atrium is the main cardiac production site, but as heart failure develops, there is a profound activation of ventricular NT-proBNP synthesis. BNP acts on distant tissues and causes diuresis, vasodilatation, and decreased renin and aldosterone secretion. Known mechanisms of BNP clearance from plasma include binding to the natriuretic peptide clearance receptor type-C and proteolysis by peptidase NEP 24.11. NT-proBNP has a longer half-life and thus higher plasma concentration than BNP. It probably is cleared from plasma by renal excretion and possibly other unknown pathways.
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PMID:NT-ProBNP: the mechanism behind the marker. 1594 7

The renin-angiotensin-aldosterone system (RAAS) is central to cardiovascular and renal physiology. However, there is no animal model in which the activation of the RAAS only reflects the activation of the angiotensin II (ANG II) AT1 receptor. As a first step to developing such a model, we characterized a gain-of-function mutant of the mouse AT1A receptor. This mutant carries two mutations: N111S predicted to activate the receptor constitutively and a COOH-terminal deletion, delta329, expected to reduce receptor internalization and desensitization. We expressed this double mutant (AT1A-N111S/delta329) in heterologous cells. It showed a pharmacological profile consistent with that of other constitutively active mutants. Furthermore, it increased basal production of inositol phosphates, as well as basal cytosolic and nuclear ERK activities. Basal proliferation of cells expressing the mutant was also greater than that of the wild type. The double mutant was poorly internalized and failed to recruit beta-arrestin 2 in the presence of ANG II. It also showed hypersensitive and hyperreactive responses to ANG II for both inositol phosphate production and ERK activation. The additivity of the phenotypes of the two mutations makes this mutant an appropriate candidate to test the physiological consequences of the AT1A receptor activation itself in transgenic animal models.
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PMID:The AT1A receptor "gain-of-function" mutant N111S/delta329 is both constitutively active and hyperreactive to angiotensin II. 1633 20

The renin-angiotensin system is a central component of the physiological and pathological responses of cardiovascular system. Its primary effector hormone, angiotensin II (ANG II), not only mediates immediate physiological effects of vasoconstriction and blood pressure regulation, but is also implicated in inflammation, endothelial dysfunction, atherosclerosis, hypertension, and congestive heart failure. The myriad effects of ANG II depend on time (acute vs. chronic) and on the cells/tissues upon which it acts. In addition to inducing G protein- and non-G protein-related signaling pathways, ANG II, via AT(1) receptors, carries out its functions via MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases [PDGF, EGFR, insulin receptor], and nonreceptor tyrosine kinases [Src, JAK/STAT, focal adhesion kinase (FAK)]. AT(1)R-mediated NAD(P)H oxidase activation leads to generation of reactive oxygen species, widely implicated in vascular inflammation and fibrosis. ANG II also promotes the association of scaffolding proteins, such as paxillin, talin, and p130Cas, leading to focal adhesion and extracellular matrix formation. These signaling cascades lead to contraction, smooth muscle cell growth, hypertrophy, and cell migration, events that contribute to normal vascular function, and to disease progression. This review focuses on the structure and function of AT(1) receptors and the major signaling mechanisms by which angiotensin influences cardiovascular physiology and pathology.
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PMID:Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. 1687 Aug 27

The precise mechanism by which cytokines such as IL-1beta negatively modulate expression of the renin gene remains incomplete. IL-1beta can repress renin transcription under both baseline and retinoic acid-stimulated conditions in As4.1 cells, a renin-expressing cell line derived from the kidney. This repression does not require a negative regulatory element present in the renin enhancer but is optimal in the presence of the entire renin enhancer. Three tandem copies of the retinoic acid response element is sufficient to attenuate the retinoic acid-response by IL-1beta. The decrease in retinoic acid-induced renin promoter activity in response to IL-1beta was blocked with the general tyrosine kinase inhibitor Genistein. IL-1beta caused an increase in the phosphorylation of ERK, but not p38MAPK or c-Jun N-terminal kinase. PD98059, an Erk kinase inhibitor, significantly decreased IL-1beta-mediated phosphorylation of ERK1/2, and attenuated the repression of baseline renin transcription in response to IL-1beta. PD98059 partially reversed the IL-1beta effect on retinoic acid-mediated transcription. To further investigate this mechanism, we searched the downstream effectors of ERK1/2 pathway. Although there was no effect of IL-1beta on the phosphorylation of ELK, Janus kinase 2, or signal transducers and activators of transcription (STAT) 1, IL-1beta significantly increased tyrosine-phosphorylation of STAT3, an effect attenuated by PD98059. STAT3 overexpression significantly repressed transcription of the renin gene, whereas small interfering RNA-mediated knockdown of STAT3 increased renin at baseline and attenuated the IL-1beta response. We conclude that in As4.1 cells, IL-1beta down-regulates renin gene expression via a mechanism involving the Erk-STAT3 pathway.
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PMID:Interleukin-1beta attenuates renin gene expression via a mitogen-activated protein kinase kinase-extracellular signal-regulated kinase and signal transducer and activator of transcription 3-dependent mechanism in As4.1 cells. 1695 49

We previously reported that angiotensin II type 1 receptor (AT1R) blockade attenuates renal inflammation/fibrogenesis in immune-mediated glomerulonephritis via angiotensin II type 2 receptor (AT2R). In the present study, further in vivo experiments revealed that AT2R was expressed in tubular epithelial cells of nephritic kidneys in mice, and feedback activation of the renin-angiotensin system during AT1R blockade significantly reduced p-ERK, but not intranuclear nuclear factor-kappaB, levels via AT2R. This led to reduction in mRNA levels of the proinflammatory mediator monocyte chemoattractant protein-1 and overall interstitial inflammation and subsequent fibrogenesis. Specific blockade of ERK expression in tubular epithelium by anti-sense oligodeoxynucleotides also attenuated interstitial inflammation, mimicking the anti-inflammatory action of AT2R in nephritic kidneys. Alternatively, we succeeded in confirming such an AT(2)R function by demonstrating that AT1R blockade did not confer renoprotection in nephritic, AT2R gene-deficient mice. Additional in vitro experiments revealed that AT2R activation did not affect nuclear factor-kappaB activation by tumor necrosis factor-alpha in cultured tubular epithelial cells, although it inhibited ERK phosphorylation, which reduced monocyte chemoattractant protein-1 mRNA levels. These results suggest that feedback activation of AT2Rs in tubular epithelium of nephritic kidneys plays an important role in attenuating interstitial inflammation.
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PMID:A possible anti-inflammatory role of angiotensin II type 2 receptor in immune-mediated glomerulonephritis during type 1 receptor blockade. 1707 82

Adipose tissue synthesizes all components of the renin-angiotensin system. The renin receptor (RenR) is able, on renin binding, to increase its efficiency to generate angiotensin I from angiotensinogen. We demonstrate that RenR is specifically synthesized in the stromal portion of human adipose tissue in both isolated interadipocyte stromal cells and in stromal areas. RenR is expressed at the periphery of cells, strongly suggesting a membranal localization. RenR protein expression in primary cultures of human stromal cells decreased significantly during differentiation, whereas RenR mRNA levels did not change, demonstrating that RenR was expressed in both preadipocyte and nonpreadipocyte cells, and was regulated at a posttranscriptional level. Double-labeling immunohistochemistry of human adipose tissue sections revealed that RenR was colocalized with renin, whereas incubation of 3T3-L1, a preadipocyte cell line, with renin stimulated the phosphorylation state of the intracellular signaling pathway ERK 1/2, and short exposure of human adipose stromal cells in primary culture to renin was followed by a long-lasting dose-dependent increase of angiotensin I generation, indicating that adipose RenR is functional. We show, using a large set of human adipose tissue biopsies, that RenR expression was increased in visceral compared with subcutaneous adipose tissue of lean and obese patients. Taken together with our finding that RenR was colocalized with plasminogen activator inhibitor type 1, the main inhibitor of the fibrinolytic system in visceral adipose tissue, the above-mentioned data suggest that RenR plays a role in obesity-induced visceral adipose tissue accumulation and its accompanying cardiovascular complications.
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PMID:Renin receptor expression in human adipose tissue. 1719 44

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


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