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      Regulation of mitochondrial dynamics in acute kidney injury in cell culture and rodent models.

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          Abstract

          The mechanism of mitochondrial damage, a key contributor to renal tubular cell death during acute kidney injury, remains largely unknown. Here, we have demonstrated a striking morphological change of mitochondria in experimental models of renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. This change contributed to mitochondrial outer membrane permeabilization, release of apoptogenic factors, and consequent apoptosis. Following either ATP depletion or cisplatin treatment of rat renal tubular cells, mitochondrial fragmentation was observed prior to cytochrome c release and apoptosis. This mitochondrial fragmentation was inhibited by Bcl2 but not by caspase inhibitors. Dynamin-related protein 1 (Drp1), a critical mitochondrial fission protein, translocated to mitochondria early during tubular cell injury, and both siRNA knockdown of Drp1 and expression of a dominant-negative Drp1 attenuated mitochondrial fragmentation, cytochrome c release, caspase activation, and apoptosis. Further in vivo analysis revealed that mitochondrial fragmentation also occurred in proximal tubular cells in mice during renal ischemia/reperfusion and cisplatin-induced nephrotoxicity. Notably, both tubular cell apoptosis and acute kidney injury were attenuated by mdivi-1, a newly identified pharmacological inhibitor of Drp1. This study demonstrates a rapid regulation of mitochondrial dynamics during acute kidney injury and identifies mitochondrial fragmentation as what we believe to be a novel mechanism contributing to mitochondrial damage and apoptosis in vivo in mouse models of disease.

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          Author and article information

          Journal
          J Clin Invest
          The Journal of clinical investigation
          American Society for Clinical Investigation
          1558-8238
          0021-9738
          May 2009
          : 119
          : 5
          Affiliations
          [1 ] Department of Cellular Biology and Anatomy, Medical College of Georgia, and Charlie Norwood VA Medical Center, Augusta, 30912, USA.
          Article
          37829
          10.1172/JCI37829
          2673870
          19349686
          f8156e48-e0ed-47ce-89d4-e0e990f1131e
          History

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