ANG II-induced tyrosine phosphorylation stimulates phospholipase C-gamma 1 and Cl-channels in mesangial cells

Abstract

Angiotensin II (ANG II)-induced, activation of phospholipase C (PLC) and Ca(2+)-dependent Cl-channels is an important signal transduction pathway for mesangial cell contraction and growth. Although ANG II receptors are traditionally though to be G protein coupled, recent evidence suggests that they may also mediate protein tyrosine phosphorylation. In cultured rat mesangial cells, 10(-7) MANG II stimulated the tyrosine phosphorylation of PLC-gamma 1 and elevation of intracellular inositol 1,4,5-trisphosphate (IP3) and Ca2+ levels; peak response occurred within 0.5 min. In cell-attached patches, ANG II stimulated the activity of Ca(2+)-dependent, 3- to 4-pS Cl-channels (number of channels x open probability) from 0.063 +/- 0.022 to 0.77 +/- 0.20. Tyrosine kinase inhibition with genistein or herbimycin A blocked all four ANG II-induced responses. We conclude the following. 1) Stimulation of inositol phosphate hydrolysis by PLC, release of IP3-dependent intracellular Ca2+ stores, and activation of Ca(2+)-dependent C1-channels by ANG II are 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 glomerular mesangial cells.