Protein kinase C inhibitors potentiate angiotensin II-induced phosphoinositide hydrolysis and intracellular Ca2+ mobilization in renal mesangial cells.
Stimulation of mesangial cells with angiotensin II leads to rapid phosphoinositide hydrolysis and subsequent mobilization of intracellular Ca2+. Previous studies indicated that activation of protein kinase C (PKC) triggers a negative-feedback signal, which limits phosphoinositide turnover. By comparing the relative susceptibility of PKC isoenzymes to phorbol ester-induced down-regulation with the down-regulation of the functional cell response, i.e. feedback inhibition of inositol trisphosphate production, we inferred that PKC-alpha and PKC-delta are candidates for regulating phosphoinositide hydrolysis in mesangial cells. To test this hypothesis further, we examined the effects of inhibitors of PKC, that are reportedly not active on PKC-delta, on angiotensin II-stimulated phosphoinositide degradation and Ca2+ mobilization. Pretreatment of mesangial cells with the PKC inhibitors staurosporine and K252a potently augmented inositol trisphosphate and 1,2-diacylglycerol formation as well as Ca2+ mobilization in response to angiotensin II. These results suggest that PKC-alpha, but not PKC-delta, is the most likely candidate mediating feedback inhibition of angiotensin II-stimulated phosphoinositide turnover in mesangial cells.
Ochsner
M
M
Photophysics Department, Ciba-Geigy Ltd., Basel, Switzerland.
Huwiler
A
A
Fleck
T
T
Pfeilschifter
J
J
D000470:Alkaloids / Q000494:pharmacology; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006868:Hydrolysis; D026121:Indole Alkaloids; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D013050:Spectrometry, Fluorescence; D019311:Staurosporine
D000470:Alkaloids; D002227:Carbazoles; D026121:Indole Alkaloids; D007527:Isoenzymes; D000804:Angiotensin II; D015544:Inositol 1,4,5-Trisphosphate; C049985:staurosporine aglycone; D011493:Protein Kinase C; D019311:Staurosporine; D002118:Calcium