ANG II-induced tyrosine phosphorylation stimulates phospholipase C-gamma 1 and Cl-channels in mesangial cells.
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.
Marrero
M B
MB
Renal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Schieffer
B
B
Ma
H
H
Bernstein
K E
KE
Ling
B N
BN
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D018118:Chloride Channels / Q000187:drug effects* / Q000378:metabolism*; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D007425:Intracellular Membranes / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D051966:Phospholipase C gamma; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D010738:Type C Phospholipases / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D018118:Chloride Channels; D007527:Isoenzymes; D000804:Angiotensin II; D014443:Tyrosine; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium