Li Wen, Du Mengmeng, Wang Qingzhu, Ma Xiaojun, Wu Lina, Guo Feng, Ji Hongfei, Huang Fengjuan, Qin Guijun
Department of Endocrinology and Metabolism, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
Institute of Clinical Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China.
Endocrinology. 2017 Jul 1;158(7):2155-2167. doi: 10.1210/en.2016-1970.
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.
我们最近发现，叉头框O1类（FoxO1）激活可通过防止大鼠肾皮质线粒体功能障碍来保护其免受高糖诱导的损伤。此外，据报道，FoxO1可介导推定激酶1（PINK1）转录，并在小鼠心肌细胞中响应线粒体氧化应激促进自噬。在本研究中，我们确定了在肾皮质中过表达FoxO1是否能逆转动物模型中已建立的糖尿病肾病。在小鼠足细胞中评估了FoxO1对线粒体自噬信号通路的影响。在雄性KM小鼠中进行了体内实验。使用链脲佐菌素（STZ）诱导的1型糖尿病（T1D）小鼠模型，并将慢病毒载体注入肾皮质以过表达FoxO1。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基因改造。我们发现线粒体形态异常和三磷酸腺苷生成减少。这些线粒体异常是由于10号染色体上磷酸酶/张力蛋白同源物减少导致的PINK1/帕金依赖性信号通路介导的线粒体自噬减少所致。FoxO1上调和PINK1/帕金途径激活可分别恢复STZ诱导的T1D小鼠中受损的足细胞。我们的结果将FoxO1的抗氧化活性与PINK1/帕金诱导的线粒体自噬联系起来，表明FoxO1在糖尿病肾病中具有新的作用。
