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Inhibition of apoptosis by Zn²⁺ in renal tubular cells following ATP depletion

Departments of ¹Cellular Biology and Anatomy and ²Physiology, Medical College of Georgia, Augusta 30912; and ³Medical Research Service, Department of Veterans Affairs Medical Center, Augusta, Georgia 30904

Submitted 17 March 2004 ; accepted in final form 21 April 2004

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. ATP depletion induced apoptosis in cultured renal tubular cells, which was accompanied by caspase activation. Zn²⁺ at 10 µM inhibited both apoptosis and caspase activation, whereas 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.

ischemia; renal tubule

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