Inhibition of apoptosis by Zn2+ in renal tubular cells following ATP depletion.
Apoptosis has been implicated in ischemic renal injury. Thus one strategy of renal protection is to antagonize apoptosis. However, apoptosis inhibitory approaches remain to be fully explored. Zn(2+) has long been implicated in apoptosis inhibition; but systematic analysis of the inhibitory effects of Zn(2+) is lacking. Moreover, whether Zn(2+) blocks renal cell apoptosis following ischemia is unknown. Here, we demonstrate that Zn(2+) is a potent apoptosis inhibitor in an in vitro model of renal cell ischemia. ATP depletion induced apoptosis in cultured renal tubular cells, which was accompanied by caspase activation. Zn(2+) at 10 microM inhibited both apoptosis and caspase activation, whereas Co(2+) was without effect. In ATP-depleted cells, Zn(2+) partially prevented Bax activation and cytochrome c release from mitochondria. In isolated cell cytosol, Zn(2+) blocked cytochrome c-stimulated caspase activation at low-micromolar concentrations. In addition, Zn(2+) could directly antagonize the enzymatic activity of purified recombinant caspases. We conclude that Zn(2+) is a potent inhibitor of apoptosis in renal tubular cells following ATP depletion. Zn(2+) blocks apoptosis at multiple steps including Bax activation, cytochrome c release, apoptosome function, and caspase activation.
Wei
Qingqing
Q
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta 30912, USA.
Wang
Jinzhao
J
Wang
Mong-Heng
MH
Yu
Fushin
F
Dong
Zheng
Z
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D000255:Adenosine Triphosphate; D045304:Cytochromes c; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D015032:Zinc