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)

This study aimed to identify the intracellular signaling pathway in angiotensin II (Ang II)-induced upregulation of plasminogen activator inhibitor type 1 (PAI-1) mRNA expression in cultured rat glomerular mesangial cells, and to examine the interaction between Ang II and TGF-beta signaling. Ang II-induced upregulation of PAI-1 mRNA expression was prevented by a protein kinase C (PKC) inhibitor, bisindorylmaleimide I. While phorbol 12-myristate 13-acetate (PMA) upregulated the PAI-1 mRNA expression, a calcium ionophore, ionomycin, had little effect. Mesangial cells pretreated with PMA for 24 h to downregulate PKC demonstrated attenuated response to Ang II. A protein tyrosine kinase inhibitor, genistein, completely blocked both Ang II- and PMA-induced PAI-1 mRNA expression. Transforming growth factor-beta1 (TGF-beta1) alone induced the expression, and in the presence of Ang II, TGF-beta1 superinduced PAI-1 mRNA expression to a higher extent. Both bisindorylmaleimide I and genistein suppressed the Ang II plus TGF-beta1-induced PAI-1 mRNA upregulation to the basal level, while downregulation of PKC attenuated the synergistic upregulation of PAI-1 mRNA expression to the level comparable to TGF-beta1 alone. These data suggest that, in rat mesangial cells, (1) PKC and protein tyrosine kinase(s) are involved in the Ang II signaling cascade, (2) protein tyrosine kinase(s) works downstream from PKC in the cascade, and (3) there is an interaction between the Ang II and TGF-beta signal pathways downstream from PKC. In in vivo settings, local activation of renin-angiotensin and TGF-beta systems in the glomeruli may synergistically augment PAI-1 expression, promote mesangial matrix accumulation and progression of glomerular injury.
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PMID:Association of TGF-beta signaling in angiotensin II-induced PAI-1 mRNA upregulation in mesangial cells: role of PKC. 1020 1

The renin-angiotensin system is one of the major cardiovascular systems that controls blood volume, peripheral vascular tone, and blood pressure. Recent studies indicate important roles for angiotensin II in inflammation, atherosclerosis, and congestive heart failure as well. It is gradually becoming clear that angiotensin II exerts effects on the cardiovascular system through several unique mechanisms, including the availability of two different angiotensin II receptors, recruitment of protein tyrosine kinase activity, and receptor tyrosine kinase transactivation. This review discusses the diverse mechanisms of angiotensin II-mediated signal transduction pathways and the various effects of angiotensin II on the cardiovascular system.
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PMID:Angiotensin II-mediated signal transduction pathways. 1188 73

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

1. Although the systemic and cardiac renin-angiotensin systems are known to be activated in the setting of pressure overload, the actions and signaling mechanisms of angiotensin (Ang) II via AT(1) and AT(2) receptors in hypertrophic cardiomyocytes (CM) remain largely unclear. 2. Hypertrophic CM were prepared from rats with aortic banding for 8 weeks, cultured and then treated as follows: (i) 1 micromol/L AngII for 24 h; (ii) 10 micromol/L losartan (an AT(1) receptor antagonist) for 1 h followed by 1 micromol/L AngII for 24 h; and (iii) 10 micromol/L PD123319 (an AT(2) receptor antagonist) for 1 h followed by 1 micromol/L AngII for 24 h. Changes in the expression of genes following stimulation of AT(1) and AT(2) receptors specific to G-protein-coupled receptor (GPCR) signaling pathways were tested using GEArray (Superarray, Bethesda, MD, USA). The effects of AngII, acting via AT(1) and AT(2) receptors, on the expression of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 were confirmed by reverse transcription-polymerase chain reaction and radioimmunoassay. 3. The genes regulated via stimulation of AT(1) receptors were mainly restricted to the signaling pathways including cAMP/protein kinase (PK) A, Ca(2+), PKC, protein tyrosine kinase, mitogen-activated protein kinases, phosphatidylinositol 3-kinase and nuclear factor-kappaB. In addition to these pathways related to activation of AT(1) receptors, four additional signaling pathways were found to be associated with stimulation of AT(2) receptors, including phospholipase C, nitric oxide/cGMP, Rho and Janus kinase/signal transducer and activator of transcription. Blockade of AT(2) receptors decreased the mRNA and protein expression of TNF-alpha and IL-1beta, whereas blockade of AT(1) receptors had no such effect. 4. In conclusion, in hypertrophic CM, AngII leads to distinct signaling responses mediated by AT(1) and AT(2) receptors. Stimulation of AT(2) receptors appears to have a greater influence on GPCR-signaling than stimulation of AT(1) receptors. Angiotensin II enhances the synthesis and secretion of TNF-alpha and IL-1beta in hypertrophic CM, which is mediated by AT(2), but not AT(1), receptors.
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PMID:Angiotensin II receptors subtypes mediate diverse gene expression profile in adult hypertrophic cardiomyocytes. 1788 Mar 76