FoxO1 Promotes Mitophagy in the Podocytes of Diabetic Male Mice via the PINK1/Parkin Pathway
FoxO1 Promotes Mitophagy in the Podocytes of Diabetic Male Mice via the PINK1/Parkin Pathway
复制标题
FoxO1 通过 PINK1/Parkin 通路促进糖尿病雄性小鼠足细胞的线粒体自噬
DOI：
10.1210/en.2016-1970
复制
发表时间：
2017-07-01
期刊：
影响因子：
4.8
通讯作者：
Qin, Guijun
中科院分区：
文献类型：
--
作者：
Li, Wen;Du, Mengmeng;Qin, Guijun
我们最近发现，叉头盒类O 1（FoxO 1）的激活保护对高葡萄糖诱导的损伤，防止大鼠肾皮质线粒体功能障碍。此外，FoxO 1已被报道介导推定激酶1（PINK 1）转录，并促进自噬反应的线粒体氧化应激在小鼠心肌细胞。在这项研究中，我们确定是否在肾脏皮质过表达FoxO 1逆转预先建立的糖尿病肾病动物模型。在小鼠足细胞中评估FoxO 1对线粒体自噬信号通路的影响。在雄性KM小鼠中进行体内实验。使用链脲佐菌素（STZ）诱导的1型糖尿病（T1 D）小鼠模型，将慢病毒载体注射到肾皮质中以过表达FoxO 1。用高浓度葡萄糖处理小鼠足细胞系，并使用慢病毒载体进行遗传修饰。我们发现异常的线粒体形态和减少腺苷三磷酸生产。这些线粒体异常是由于通过减少10号染色体上的磷酸酶/张力蛋白同源物诱导的PINK 1/Parkin依赖性信号传导减少线粒体自噬。FoxO 1上调和PINK 1/Parkin通路激活可以单独恢复STZ诱导的T1 D小鼠中受损的足细胞。我们的研究结果将FoxO 1的抗氧化活性与PINK 1/Parkin诱导的线粒体自噬联系起来，表明FoxO 1在糖尿病肾病中的新作用。
We recently showed that forkhead-box class O1 (FoxO1) activation protects against high glucose-induced injury by preventing mitochondrial dysfunction in the rat kidney cortex. In addition, FoxO1 has been reported to mediate putative kinase 1 (PINK1) transcription and promote autophagy in response to mitochondrial oxidative stress in murine cardiomyocytes. In this study, we ascertained whether overexpressing FoxO1 in the kidney cortex reverses preestablished diabetic nephropathy in animal models. The effect of FoxO1 on mitophagy signaling pathways was evaluated in mouse podocytes. In vivo experiments were performed in male KM mice. A mouse model of streptozotocin (STZ)-induced type 1 diabetes (T1D) was used, and lentiviral vectors were injected into the kidney cortex to overexpress FoxO1. A mouse podocyte cell line was treated with high concentrations of glucose and genetically modified using lentiviral vectors. We found aberrant mitochondrial morphology and reduced adenosine triphosphate production. These mitochondrial abnormalities were due to decreased mitophagy via reduced phosphatase/tensin homolog on chromosome 10-induced PINK1/Parkin-dependent signaling. FoxO1 upregulation and PINK1/Parkin pathway activation can individually restore injured podocytes in STZ-induced T1D mice. Our results link the antioxidative activity of FoxO1 with PINK1/Parkin-induced mitophagy, indicating a novel role of FoxO1 in diabetic nephropathy.