II induces apoptosis in renal proximal tubular cells. Am J Physiol Renal Physiol 284: F955-F965, 2003; 10.1152/ajprenal.00246.2002-ANG II has been demonstrated to play a role in the progression of tubulointerstial injury. We studied the direct effect of ANG II on apoptosis of cultured rat renal proximal tubular epithelial cells (RPTECs). ANG II promoted RPTEC apoptosis in a dose-and time-dependent manner. This effect of ANG II was attenuated by anti-transforming growth factor (TGF)-␤ antibody. Moreover, TGF-␤ triggered RPTEC apoptosis in a dose-dependent manner. ANG II also enhanced RPTEC expression of Fas and Fas ligand (FasL); furthermore, anti-FasL antibody attenuated ANG II-induced RPTEC apoptosis. In addition, ANG II increased RPTEC expression of Bax, a cell death protein. Both ANG II type 1 (AT1) and type 2 (AT2) receptor blockers inhibited ANG II-induced RPTEC apoptosis. SB-202190, an inhibitor of p38 MAPK phosphorylation, and caspase-3 inhibitor also attenuated ANG II-induced RPTEC apoptosis. ANG II enhanced RPTEC heme oxygenase (HO)-1 expression. Interestingly, pretreatment with hemin as well as curcumin (inducers of HO-1) inhibited the ANG II-induced tubular cell apoptosis; conversely, pretreatment with zinc protoporphyrin, an inhibitor of HO-1 expression, promoted the effect of ANG II. These results suggest that ANG II-induced apoptosis is mediated via both AT1 and AT2 receptors through the generation of TGF-␤, followed by the transcription of cell death genes such as Fas, FasL, and Bax. Modulation of tubular cell expression of HO-1 has an inverse relationship with the ANG II-induced tubular cell apoptosis.Bax; Bcl-2; Fas; Fas ligand; proximal tubular epithelial cells; heme oxygenase-1 ANG II HAS BEEN DEMONSTRATED to contribute to the progression of renal injury through its hemodynamic effects (35, 36). These effects are confirmed by blocking its production and receptor sites (15,16,20). However, apart from its hemodynamic effects, the direct effects of ANG II on kidney cells are being increasingly recognized (2,6,9,25,27). It has been demonstrated that in addition to circulating ANG II, tissue (intrarenal) generation of ANG II is also important for its net effect (35).Tubulointerstitial lesions have been demonstrated to correlate with the progression of renal failure (5,11,18,21,26), thus suggesting their contribution to the progression of renal failure (11). Transforming growth factor (TGF)-␤, a fibrogenic cytokine, has been shown to play a role in the inception and progression of renal lesions in both human renal diseases and experimental animal models of human immunodeficiency virus-associated nephropathy, renal ablation, and ureteric obstruction (16,33,36). Interestingly, in these conditions, elevated blood ANG II levels have been reported. Moreover, modalities, which inhibit the production of ANG II, have been demonstrated to slow the progression of renal lesions (15,16,20).The effect of ANG II on the growth of proximal tubular cells has been evaluated in both in vivo and in vitro studies (4, 3...