ANGIOTENSIN-II STIMULATION OF THE STRESS-ACTIVATED PROTEIN-KINASES INRENAL MESANGIAL CELLS IS MEDIATED BY THE ANGIOTENSIN AT(1) RECEPTOR SUBTYPE

Treatment of renal mesangial cells with the vasoconstrictor angiotensi n 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 activatio n 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 act ivity is observed, clearly implying the AT(1)-receptor in this angiote nsin II-mediated response. To further elucidate the mechanism involved in angiotensin II-induced SAPK activation, cells were treated with di fferent inhibitors. Genistein, a tyrosine kinase inhibitor, greatly bl ocks (by 90%) the angiotensin II response, whereas pertussis toxin onl y partially inhibits angiotensin II-activated SAPK activity (by 76%). A highly potent protein kinase C inhibitor propyl-1H-indoyl-3-yl]-3-(1 -methyl-1H-indoyl-3-yl) maleimide methane sulfonate), Ro 31-8220, as w ell as protein kinase C depletion from the cells by prolonged phorbol ester pretreatment, fail to inhibit the angiotensin II-induced SAPK ac tivation. In summary these results suggest that angiotensin II AT(1)-r eceptor is able to activate the SAPK cascade in mesangial cells by a p athway independent of protein kinase C, but requiring both pertussis-t oxin-sensitive and -insensitive G-proteins and tyrosine kinase activat ion. (C) 1998 Elsevier Science B.V.