Angiotensin II induces apoptosis in renal proximal tubular cells

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)-beta antibody. Moreover, TGF-beta 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 ( AT(1)) and type 2 ( AT(2)) 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 AT(1) and AT(2) receptors through the generation of TGF- beta, 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.