FoxO1 Promotes Mitophagy in the Podocytes of Diabetic Male Mice via the PINK1/Parkin Pathway

• Published in: Endocrinology (Philadelphia) 2017-07, Vol.158 (7), p.2155-2167
• Main Authors: Li, Wen, Du, Mengmeng, Wang, Qingzhu, Ma, Xiaojun, Wu, Lina, Guo, Feng, Ji, Hongfei, Huang, Fengjuan, Qin, Guijun
• Format: Article
• Language: English
• Subjects: Aberration; Abnormalities; Activation; Adenosine triphosphate; Animal models; Animals; ATP; Autophagy; Cardiomyocytes; Cells, Cultured; Chromosome 10; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - pathology; Diabetic Nephropathies - genetics; Diabetic Nephropathies - pathology; Diabetic nephropathy; Endocrinology; Forkhead Box Protein O1 - physiology; Forkhead protein; FOXO1 protein; Genetic modification; Glucose; Homology; In vivo methods and tests; Injury prevention; Kidneys; Kinases; Male; Males; Mice; Mitochondria; Mitochondria - physiology; Mitochondrial Degradation - genetics; Mitophagy; Nephropathy; Oxidative stress; Parkin protein; Phagocytosis; Podocytes - physiology; Protein Kinases - genetics; Protein Kinases - physiology; PTEN-induced putative kinase; Reactive Oxygen Species - metabolism; Renal cortex; Rodents; Signal transduction; Signal Transduction - genetics; Signaling; Streptozocin; Tensin; Transcription; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - physiology
• ISSN: 0013-7227; 1945-7170
• 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.FoxO1 is sufficient to promote mitochondrial dysfunction and podocyte injury under high-glucose conditions with an increased level of PINK1.