Angiotensin II stimulation of the stress-activated protein kinases in renal mesangial cells is mediated by the angiotensin AT1 receptor subtype.
Treatment of renal mesangial cells with the vasoconstrictor angiotensin II 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 AT1 receptor antagonist valsartan, a concentration-dependent inhibition of angiotensin II-induced SAPK activity is observed, clearly implying the AT1-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 AT1-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.
Huwiler
A
A
Center for Biomembranes and Lipid Enzymology, University of Utrecht, The Netherlands.
van Rossum
G
G
Wartmann
M
M
Pfeilschifter
J
J
D000803:Angiotensin I / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D007211:Indoles / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007211:Indoles; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D000803:Angiotensin I; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C064758:Ro 31-8220