Angiotensin II stimulation of the stress-activated protein kinases in renal mesangial cells is mediated by the angiotensin AT1 receptor subtype

被引:20
作者
Huwiler, A
van Rossum, G
Wartmann, M
Pfeilschifter, J
机构
[1] Univ Frankfurt Klinikum, Zeneca Pharmakol, D-60590 Frankfurt, Germany
[2] Univ Utrecht, Ctr Biomembranes & Lipid Enzymol, NL-3584 CH Utrecht, Netherlands
[3] Novartis Ltd, Res Dept, Div Pharmaceut, CH-4002 Basel, Switzerland
关键词
angiotensin II; angiotensin AT(1) receptor; stress-activated protein kinase; mesangial cell;
D O I
10.1016/S0014-2999(97)01542-2
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Treatment of renal mesangial cells with the vasoconstrictor angiotensin Il stimulates a concentration-dependent increase in stress-activated protein kinase (SAPK) activity as measured by phosphorylation of the substrate c-Jun. Time course studies reveal a transient SAPK activation by angiotensin II which is maximal after 5-10 min of stimulation and rapidly declines thereafter to basal levels within 30 min. Using the highly selective angiotensin II AT(1) receptor antagonist valsartan, a concentration-dependent inhibition of angiotensin II-induced SAPK activity is observed, clearly implying the AT(1)-receptor in this angiotensin II-mediated response. To further elucidate the mechanism involved in angiotensin II-induced SAPK activation, cells were treated with different inhibitors. Genistein, a tyrosine kinase inhibitor, greatly blocks (by 90%) the angiotensin II response, whereas pertussis toxin only partially inhibits angiotensin II-activated SAPK activity (by 76%). A highly potent protein kinase C inhibitor {3-[1-[3-(amidinothio)propyl-1H-indoyl-3-yl]-3-(1-methyl-1H-indoyl-3-yl) maleimide methane sulfonate), Ro 31-8220, as well as protein kinase C depletion from the cells by prolonged phorbol ester pretreatment, fail to inhibit the angiotensin II-induced SAPK activation. In summary these results suggest that angiotensin II AT(1)-receptor is able to activate the SAPK cascade in mesangial cells by a pathway independent of protein kinase C, but requiring both pertussis-toxin-sensitive and -insensitive G-proteins and tyrosine kinase activation. (C) 1998 Elsevier Science B.V.
引用
收藏
页码:297 / 302
页数:6
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