Angiotensin II AT(2) receptors inhibit growth responses in proximal tubule cells

Angiotensin II (ANG II) subtype 2 (AT(2)) receptors are expressed in the adult kidney, but the effects of AT(2) receptor activation are unclear. The proximal tubule cell line LLC-PK(1) was transfected with a plasmid containing cDNA for the rat AT(2) receptor. In transfected cells, specific binding of (125)I-labeled ANG II was detected (dissociation constant = 0.81 nM), with inhibition by the AT(2) antagonist PD-123319, and no effect of the AT(1) antagonist losartan. ANG II (10(-7) M) significantly inhibited mitogen-activated protein kinase (MAPK) activity in transfected cells, associated with decreased phosphorylation of the extracellular signal-related kinases ERK1 and ERK2. ANG II stimulated phosphotyrosine phosphatase activity within 5 min, an effect blocked by PD-123319 and the phosphatase inhibitor vanadate. In transfected cells, ANG II inhibited epidermal growth factor-stimulated [(3)H]thymidine incorporation, an effect reversed by vanadate. In contrast, vanadate did not block ANG II-stimulated apoptosis of transfected cells. In summary, AT(2) receptors in proximal tubule cells inhibit MAPK activity and stimulate phosphotyrosine phosphatase. AT(2) receptor-induced inhibition of mitogenesis is mediated by phosphatase activation, whereas effects on apoptosis are insensitive to phosphatase inhibition. The data suggest that AT(2) receptors inhibit cell growth via distinct signaling pathways in the proximal tubule.