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Am J Physiol Renal Physiol (April 27, 2004). doi:10.1152/ajprenal.00083.2004
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Submitted on March 17, 2004
Accepted on April 21, 2004

Inhibition of Apoptosis by Zn2+ in Renal Tubular Cells Following ATP-depletion

Qingqing Wei1, Jinzhao Wang1, Mong-Heng Wang2, Fushin Yu1, and Zheng Dong3*

1 Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA, USA
2 Department of Physiology, Medical College of Georgia, Augusta, GA, USA
3 Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA, USA; Medical Research Service, Department of Veterans Affairs Medical Center, Augusta, GA, USA

* To whom correspondence should be addressed. E-mail: zdong{at}mail.mcg.edu.

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. Zn2+ has long been implicated in apoptosis inhibition; but systematic analysis of the inhibitory effects of Zn2+ is lacking. Moreover, whether Zn2+ blocks renal cell apoptosis following ischemia is unknown. Here we demonstrate that Zn2+ is a potent apoptosis inhibitor in an in vitro model of renal cell ischemia. ATPdepletion induced apoptosis in cultured renal tubular cells, which was accompanied by caspase activation. Zn2+ at 10µM inhibited both apoptosis and caspase activation, while Co2+ was without effect. In ATP-depleted cells, Zn2+ partially prevented Bax activation and cytochrome c release from mitochondria. In isolated cell cytosol, Zn2+ blocked cytochrome c-stimulated caspase activation at low micromolar concentrations. In addition, Zn2+ could directly antagonize the enzymatic activity of purified recombinant caspases. We conclude that Zn2+ is a potent inhibitor of apoptosis in renal tubular cells following ATP-depletion. Zn2+ blocks apoptosis at multiple steps including Bax activation, cytochrome c release, apoptosome function and caspase activation.




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