Podocyte-Specific Loss of Kruppel-Like Factor 6 Increases Mitochondrial Injury in Diabetic Kidney Disease
Podocyte-Specific Loss of Kruppel-Like Factor 6 Increases Mitochondrial Injury in Diabetic Kidney Disease
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DOI：
10.2337/db17-0958
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发表时间：
2018-11-01
期刊：
影响因子：
7.7
通讯作者：
Mallipattu, Sandeep K.
中科院分区：
文献类型：
--
作者：
Horne, Sylvia J.;Vasquez, Jessica M.;Mallipattu, Sandeep K.
在几种小鼠模型以及糖尿病肾病（DKD）个体中均观察到线粒体损伤。虽然新出现的证据已经强调了关键的转录调控在线粒体生物合成中的作用，但对糖尿病条件下足细胞中线粒体细胞色素c氧化酶组装的调控知之甚少。我们最近报道了锌指Kruppel样因子6（KLF 6）在蛋白尿小鼠模型中维持线粒体功能和防止细胞凋亡的关键作用。在这项研究中，我们报告，足细胞特异性敲低Klf 6增加了耐药C57 BL/6小鼠品系对链脲霉素诱导的DKD的易感性。我们观察到，足细胞中KLF 6的丢失降低了细胞色素c氧化酶2的合成表达，从而增加线粒体损伤，导致糖尿病条件下内在凋亡途径的激活。相反，线粒体损伤和凋亡显着减弱与过度表达KLF 6在高血糖条件下培养的人足细胞。最后，我们观察到随着DKD的进展，人肾活检组织中KLF 6的肾小球和足细胞特异性表达显著减少。总的来说，这些数据表明，足细胞特异性KLF 6是至关重要的，以防止线粒体损伤和细胞凋亡在糖尿病条件下。
Mitochondrial injury is uniformly observed in several murine models as well as in individuals with diabetic kidney disease (DKD). Although emerging evidence has highlighted the role of key transcriptional regulators in mitochondrial biogenesis, little is known about the regulation of mitochondrial cytochrome c oxidase assembly in the podocyte under diabetic conditions. We recently reported a critical role of the zinc finger Kruppel-like factor 6 (KLF6) in maintaining mitochondrial function and preventing apoptosis in a proteinuric murine model. In this study, we report that podocyte-specific knockdown of Klf6 increased the susceptibility to streptozotocin-induced DKD in the resistant C57BL/6 mouse strain. We observed that the loss of KLF6 in podocytes reduced the expression of synthesis of cytochrome c oxidase 2 with resultant increased mitochondrial injury, leading to activation of the intrinsic apoptotic pathway under diabetic conditions. Conversely, mitochondrial injury and apoptosis were significantly attenuated with overexpression of KLF6 in cultured human podocytes under hyperglycemic conditions. Finally, we observed a significant reduction in glomerular and podocyte-specific expression of KLF6 in human kidney biopsies with progression of DKD. Collectively, these data suggest that podocyte-specific KLF6 is critical to preventing mitochondrial injury and apoptosis under diabetic conditions.