Ayanga Bernard A, Badal Shawn S, Wang Yin, Galvan Daniel L, Chang Benny H, Schumacker Paul T, Danesh Farhad R
Section of Nephrology, Department of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas;
Departments of Cell and Molecular Biology and.
J Am Soc Nephrol. 2016 Sep;27(9):2733-47. doi: 10.1681/ASN.2015101096. Epub 2016 Jan 29.
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.
线粒体分裂与糖尿病肾病（DN）的发病机制有关。然而，线粒体分裂如何在体内影响DN的进展尚不清楚。在此，我们报告了有条件地在足细胞中特异性缺失动力相关蛋白1（Drp1）（线粒体分裂的一个重要组成部分）对DN发病机制和进展的影响。在糖尿病小鼠中可诱导性地在足细胞中特异性缺失Drp1可减少蛋白尿，并改善系膜基质扩张和足细胞形态。超微结构分析显示，野生型糖尿病小鼠足细胞中碎片化线粒体显著增加，而糖尿病小鼠Drp1基因缺失的足细胞中线粒体结构有明显改善。当从糖尿病小鼠中分离并在高糖环境中培养时，与野生型足细胞相比，Drp1基因缺失的足细胞具有更长的线粒体和更好的线粒体适应性，与增强的氧消耗和ATP产生相关。此外，给予Drp1的药理学抑制剂Mdivi1可显著抑制线粒体分裂，并挽救小鼠DN的关键病理特征。综上所述，这些结果揭示了线粒体形态与DN进展之间的新关联，并指出Drp1是DN的一个潜在治疗靶点。
