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.
Bhaskaran
Madhu
M
Department of Medicine, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA.
Reddy
Krishna
K
Radhakrishanan
Neetu
N
Franki
Nicholas
N
Ding
Guohua
G
Singhal
Pravin C
PC
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D053222:Fas Ligand Protein; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases