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      Dynamin–Related Protein 1 Deficiency Improves Mitochondrial Fitness and Protects against Progression of Diabetic Nephropathy

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          Abstract

          Mitochondrial fission has been linked to the pathogenesis of diabetic nephropathy (DN). However, how mitochondrial fission affects progression of DN in vivo is unknown. Here, we report the effect of conditional podocyte–specific deletion of dynamin-related protein 1 (Drp1), an essential component of mitochondrial fission, on the pathogenesis and progression of DN. Inducible podocyte–specific deletion of Drp1 in diabetic mice decreased albuminuria and improved mesangial matrix expansion and podocyte morphology. Ultrastructure analysis revealed a significant increase in fragmented mitochondria in the podocytes of wild–type diabetic mice but a marked improvement in mitochondrial structure in Drp1-null podocytes of diabetic mice. When isolated from diabetic mice and cultured in high glucose, Drp1-null podocytes had more elongated mitochondria and better mitochondrial fitness associated with enhanced oxygen consumption and ATP production than wild-type podocytes. Furthermore, administration of a pharmacologic inhibitor of Drp1, Mdivi1, significantly blunted mitochondrial fission and rescued key pathologic features of DN in mice. Taken together, these results provide novel correlations between mitochondrial morphology and the progression of DN and point to Drp1 as a potential therapeutic target in DN.

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          Author and article information

          Journal
          J Am Soc Nephrol
          J. Am. Soc. Nephrol
          jnephrol
          jnephrol
          ASN
          Journal of the American Society of Nephrology : JASN
          American Society of Nephrology
          1046-6673
          1533-3450
          September 2016
          29 January 2016
          : 27
          : 9
          : 2733-2747
          Affiliations
          [* ]Section of Nephrology, Department of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas;
          Departments of []Cell and Molecular Biology and
          [§ ]Pharmacology, Baylor College of Medicine, Houston, Texas; and
          []Department of Pediatrics, Division of Neonatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
          Author notes
          Correspondence: Dr. Farhad R. Danesh, Section of Nephrology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Unit 1468, Houston, TX 77030. Email: fdanesh@ 123456mdanderson.org
          Article
          PMC5004662 PMC5004662 5004662 2015101096
          10.1681/ASN.2015101096
          5004662
          26825530
          Copyright © 2016 by the American Society of Nephrology
          Page count
          Figures: 5, Tables: 0, Equations: 0, References: 44, Pages: 15
          Categories
          Basic Research
          Custom metadata
          September 2016

          diabetic nephropathy, podocyte, mitochondria

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