Dynamin-Related Protein 1 Deficiency Improves Mitochondrial Fitness and Protects against Progression of Diabetic Nephropathy
Dynamin-Related Protein 1 Deficiency Improves Mitochondrial Fitness and Protects against Progression of Diabetic Nephropathy
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DOI：
10.1681/asn.2015101096
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发表时间：
2016-09-01
影响因子：
13.6
通讯作者：
Danesh, Farhad R.
中科院分区：
文献类型：
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作者：
Ayanga, Bernard A.;Badal, Shawn S.;Danesh, Farhad R.
线粒体分裂与糖尿病肾病（DN）的发病机制有关。然而，线粒体分裂如何影响体内DN的进展尚不清楚。在这里，我们报告了条件性足细胞特异性缺失动力蛋白相关蛋白1（Drp 1），线粒体分裂的重要组成部分，对DN的发病机制和进展的影响。糖尿病小鼠中可诱导的足细胞特异性Drp 1缺失可减少白蛋白尿，改善系膜基质扩张和足细胞形态。超微结构分析显示，在野生型糖尿病小鼠的足细胞中，破碎的线粒体显着增加，但在糖尿病小鼠的Drp 1无效足细胞中，线粒体结构有显着改善。当从糖尿病小鼠中分离并在高葡萄糖中培养时，Drp 1-null足细胞具有比野生型足细胞更长的线粒体和更好的线粒体适应性，与增强的耗氧量和ATP产生相关。此外，给予Drp 1的药理学抑制剂Mdivi 1显著减弱了小鼠的线粒体分裂并挽救了DN的关键病理特征。总之，这些结果提供了线粒体形态学和DN进展之间的新的相关性，并指出Drp 1作为DN的潜在治疗靶点。
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.