ANG-II-INDUCED TYROSINE PHOSPHORYLATION STIMULATES PHOSPHOLIPASE-C-GAMMA-1 AND C1(-) CHANNELS IN MESANGIAL CELLS

Angiotensin II (ANG II)-induced, activation of phospholipase C (PLC) a nd Ca2+-dependent Cl- channels is an important-signal transduction pat hway for mesangial cell contraction and growth. Although ANG II recept ors are traditionally thought to be G protein coupled, recent evidence suggests that they may also mediate protein tyrosine phosphorylation. In cultured rat mesangial cells, 10(-7) M ANG II stimulated the tyros ine phosphorylation of PLC-gamma 1 and elevation of intracellular inos itol 1,4,5-trisphosphate (IP3) and Ca2+ levels; peak response occurred within 0.5 min. In cell-attached patches, ANG II stimulated the activ ity of Ca2+-dependent, 3- to 4-pS Cl- channels (number of channels x o pen probability) from 0.063 +/- 0.022 to 0.77 +/- 0.20. Tyrosine kinas e inhibition with genistein or herbimycin A blocked all four ANG II-in duced responses. We conclude the following. 1) Stimulation of inositol phosphate hydrolysis by PLC, release of IP3-dependent intracellular C a2+ stores, and activation of Ca2+-dependent Cl- channels by ANG II ar e dependent on the tyrosine phosphorylation of PLC-gamma 1.2) This ANG II-induced signal transduction cascade provides a possible mechanism for both the contractile and growth-stimulating effects of ANG II on g lomerular mesangial cells.