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)

Nuclear factor-kappaB (NF-kappaB) regulates many genes involved in renal pathophysiologic processes. It was previously demonstrated that angiotensin II (AngII) and its amino-terminal degradation product AngIII activate NF-kappaB in mesangial cells. However, which are the Ang receptor subtypes involved in the NF-kappaB pathway and whether these Ang peptides act through the same or different receptors in mesangial cells have not been evaluated. Under the culture conditions used, quiescent rat mesangial cells expressed both AT(1) and AT(2) receptors. To investigate the receptors involved in the NF-kappaB pathway, two different approaches were used, i.e., pharmacologic studies, using specific AT(1) and AT(2) receptor antagonists and agonists, and studies in AT(1) receptor-knockout mice. In cultured rat mesangial cells, both AT(1) and AT(2) receptor antagonists inhibited AngII-induced NF-kappaB DNA binding activity, whereas NF-kappaB activation elicited by AngIII was mainly blocked by the AT(2) receptor antagonist. Similar results were observed for cytosolic IkappaBalpha degradation. An AT(2) receptor agonist also activated NF-kappaB. In AT(1) receptor-knockout murine mesangial cells, AngIII and AngII increased NF-kappaB activity and degraded cytosolic IkappaBalpha; both processes were blocked by the AT(2) receptor antagonist. These data demonstrate that, in mesangial cells, NF-kappaB activation is mediated by AT(1) and AT(2) receptors, suggesting a novel intracellular signaling mechanism for AT(2) receptors in the kidney. Some differences in Ang peptide receptor-mediated responses were also observed. AngII activates NF-kappaB via AT(1) and AT(2) receptors, whereas AngIII acts mainly via AT(2) receptors. These results suggest the potential involvement of the AngIII/AT(2) receptor/NF-kappaB pathway in pathophysiologic processes in the kidney and provide a better understanding of the renin-angiotensin system.
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PMID:Angiotensin III activates nuclear transcription factor-kappaB in cultured mesangial cells mainly via AT(2) receptors: studies with AT(1) receptor-knockout mice. 1196 Oct 3

Angiotensin-II (AII), the dominant effector of the renin-angiotensin system, is involved in the pathogenesis of cardiovascular diseases, such as atherosclerosis. Upregulation of the adhesion molecules VCAM-1, ICAM-1, and E-selectin in endothelial cells by inflammatory cytokines through nuclear factor kappa B (NFkappaB) activation is implicated in formation and progression of atherosclerotic plaque. Here we show that AII induces NFkappaB-dependent transcription in primary endothelial cell lines, leading to the upregulation of ICAM-1 and VCAM-1 expression. NFkappaB activation by AII is mediated by the NFkappaB-inducing kinase (NIK), a common mediator of NFkappaB activation by inflammatory cytokines, such as TNF-alpha. However, NFkappaB stimulation by AII differs from that of TNF-alpha since a TNF-receptor associated factor 2 (TRAF-2) dominant negative mutant does not prevent AII-mediated NFkappaB activation. In analogy with TNF-alpha-dependent activation of NFkappaB, treatment with either the anti-oxidant N-acetyl cysteine (NAC) or the cyclooxygenase (COX) inhibitor acetyl salicylic acid (aspirin), but not indometacin, prevents the induction of NFkappaB-dependent transcription by AII. Thus, production of reactive oxygen species, aspirin (asp)-sensitive enzymes of the arachidonate metabolism, and NIK are common transducers of AII- and TNF-dependent pathways to NFkappaB. AII also activates the inflammatory p38 kinase in endothelial cells, an effect inhibited by exposure to either NAC or asp. Pharmacological interference of the p38 pathway, with the inhibitor SB 202190, prevented AII-mediated activation of the NFkappaB target V-CAM, without affecting degradation of IkappaBalpha. These results support a pro-inflammatory effect of the vasoactive peptide AII in endothelial cells, through at least two pathways-NFkappaB and p38-both of which are sensitive to asp and antioxidants.
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PMID:Endothelial activation by angiotensin II through NFkappaB and p38 pathways: Involvement of NFkappaB-inducible kinase (NIK), free oxygen radicals, and selective inhibition by aspirin. 1270 49

The renin-angiotensin system (RAS) is linked with the vascular motion and the secretion of aldosterone. The purpose of the present study was to elucidate whether angiotensin II (Ang II) induces monocytes (Mo) to express tissue factor (TF) and if Ang II subtype 1 receptor (AT1R) antagonists inhibit the effect of Ang II. The roles of different intracellular signal transduction pathways and IkappaB/NF-kappaB in Ang II-induced TF expression of Mo were also studied to explore the mechanisms involved. Mo were isolated from heparinized human blood by a two-step gradient centrifugation, cultured in RPMI-1640 and exposed to Ang II and other test reagents. Mo TF activity and TF antigen were determined with a one-stage clotting method and ELISA, respectively, after the culture. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the TF mRNA levels in Mo. The level of IkappaBalpha in Mo was detected by Western blot analysis. Electrophoresis mobility shift assay (EMSA) was performed to evaluate the binding activity of NF-kappaB in Mo. The experiment results are as follows: (1) Ang II (10(-10)-10(-7) M) induced Mo to express TF activity but had no marked effect on other mononuclear cells. Ang II 10(-10)-10(-7) M) also caused increased TF mRNA expression and TF antigen from Mo in a dose-dependent manner. The TF antigen of Mo was elevated at 4 h after Mo was exposed to Ang II (10(-7) M) in culture, reached the peak at 6 h, and then declined from 12 h. The changes of TF activity were positively correlated with those of TF antigen. TF mRNA expression was elevated at 1 h, peaked at 3 h, and declined after 8 h. (2) Losartan (10(-6)-10(-5) M) significantly inhibited the stimulative effects of Ang II on TF activity, TF antigen and TF mRNA in Mo in a dose-dependent manner. (3) The protein kinase C (PKC) inhibitor, staurosporine, and the protein tyrosine kinase (PTK) inhibitor, genistein, both lowered TF levels in Mo, but the inhibitory effect of staurosporine was stronger than that of genistein. The effect of mitogen-activated protein kinase (MAPK) inhibitor, U0126, on monocytic TF expression was not significant. (4) Western blot analysis revealed that after Ang II (10(-7) M)exposure, levels of IkappaBalpha began to decrease at 15 min, reached a nadir at 60 min (P<.01), and recovered at 180 min. (5) EMSA showed that NF-kappaB binding activity started to increase at 15 min, reached a peak at 60 min, and returned to baseline at 180 min. The present data suggest that Ang II can directly induce TF expression in human Mo and this effect is mediated by AT1R. PKC may play the most important role in Ang II-induced TF expression among the three signal pathways detected. In addition, activation of NF-kappaB is also involved in the TF expression of Mo induced by Ang II.
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PMID:Angiotensin II induces the expression of tissue factor and its mechanism in human monocytes. 1595 27

Angiotensin II (Ang II) is the main active peptide of the renin-angiotensin system (RAS), producing a number of inflammatory mediators that lead to endothelial dysfunction and the progression of atherosclerosis. Ang II-induced NF-kappaB nuclear translocation plays a pivotal role in this response. This study examines the NF-kappaB activation mechanism elicited by Ang II in human umbilical vein endothelial cells (HUVEC). Electrophoretic mobility shift assays and Western blotting revealed that Ang II, signaling via AT(1), produces a time-dependent increase in NF-kappaB DNA binding and IkappaBalpha degradation. These results also demonstrate that Ang II leads to MAPK phosphorylation and p38MAPK pathway-induced NF-kappaB activation. Furthermore, AT(1) is required for p38MAPK phosphorylation induced by Ang II. This study provides evidence that Ang II elicits NF-kappaB activation via the p38MAPK pathway in HUVEC.
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PMID:Angiotensin II induces NF-kappa B activation in HUVEC via the p38MAPK pathway. 1709 93

Angiotensin II (Ang II) is the major effector peptide of the renin angiotensin system that induces inflammatory gene expression through the nuclear factor-kappaB (NF-kappaB) transcription factor. Activation of latent cytoplasmic NF-kappaB is controlled by distinct pathways, the best known being the canonical pathway controlling IkappaB kinase activation. Interestingly, Ang II only weakly activates the canonical pathway. Although basal nucleocytoplasmic RelA shuttling is required for Ang II stimulation, changes in RelA translocation do not account for its transcriptional effect. Instead, Ang II rapidly induced RelA phosphorylation at Ser residue 536, and complex formation with the Ser(536) kinase known as the NF-kappaB-inducing kinase (NIK)/MEKK14. The requirement of NIK in Ang II-inducible transcription was shown by expressing a dominant-negative NIK or small interfering RNA (siRNA)-mediated knockdown; both inhibited Ang II-induced transcription. Conversely, constitutively active NIK potently induced RelA transactivation activity. Consistent with its actions independent of the canonical pathway, NIK induces the activity of the RelA transactivation domains -1 and -2 in constitutively nuclear GAL4-RelA fusion proteins that do not bind IkappaBalpha. Ang II induces NIK activity, phosphorylation of its endogenous IkappaB kinase alpha substrate, and induction of nuclear NF-kappaB2 (p52) processing. NIK down-regulation prevents Ang II-induced phospho-Ser(536) RelA formation, indicating that it is essential for RelA activation. The Ang II pathway further involves the RhoA small GTP-binding protein because RhoA inhibition blocks Ang II-induced transcriptional activity and formation of phospho-Ser(536) RelA formation. Finally, we demonstrate that Ang II infusion in vivo rapidly induces phospho-Ser(536) RelA formation and activation of the NF-kappaB-dependent IL-6 gene. These data indicate that Ang II induces NF-kappaB-dependent transcription through an alternative pathway, being largely independent of IkappaB proteolysis, but mediated by the small GTPases Rac/RhoA, required for NIK.RelA complex formation and inducible Ser(536) RelA phosphorylation.
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PMID:Involvement of a novel Rac/RhoA guanosine triphosphatase-nuclear factor-kappaB inducing kinase signaling pathway mediating angiotensin II-induced RelA transactivation. 1759 24