title: Inhibition of apoptosis by Zn2+ in renal tubular cells following ATP depletion.
abstract: 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.
authors.affiliation: Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta 30912, USA.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wei
authors.forename: Jinzhao
authors.initials: J
authors.lastname: Wang
authors.forename: Mong-Heng
authors.initials: MH
authors.lastname: Wang
authors.forename: Fushin
authors.initials: F
authors.lastname: Yu
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
mesh_terms: 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
chemical_list: 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