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FGF13-sensitive alteration of Parkin safeguards mitochondrial homeostasis in endothelium of diabetic nephropathy

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posted on 2022-10-18, 18:12 authored by Jia Sun, Xueqiang Guan, Chao Niu, Peng Chen, Yuankuan Li, Xuejiao Wang, Lan Luo, Mengxue Liu, Yanni Shou, Xiaozhong Huang, Yan Cai, Junjie Zhu, Junfu Fan, Xiaokun Li, Litai Jin, Weitao Cong

Studies of diabetic glomerular injury raise the possibility of developing useful early biomarkers and therapeutic approaches for the treatment of type 2 diabetic nephropathy (T2DN). In this study, it is found that FGF13 expression is induced in glomerular endothelial cells (GECs) during T2DN progression. Endothelial-specific deletion of Fgf13 potentially alleviates T2DN damage, while Fgf13 overexpression has the opposite effects. Mechanistically, Fgf13 deficiency results in improved mitochondrial homeostasis and endothelial barrier integrity in T2DN. Moreover, FGF13-sensitive alteration of Parkin safeguards mitochondrial homeostasis in endothelium of diabetic nephropathy via promotion of mitophagy and inhibition of apoptosis. Additionally, it is confirmed that the beneficial effects of Fgf13 deficiency on T2DN are abolished by endothelial-specific double deletion of Fgf13 and Prkn. The effects of Fgf13 deficiency on mitophagy and apoptosis via Parkin-dependent regulation may be distinct and separable events under diabetic conditions. These data show that the bifunctional role of Fgf13 deficiency in promoting mitophagy and inhibiting apoptosis through Parkin can shape mitochondrial homeostasis regulation in GECs and T2DN progression. Acting as a potential therapeutic target for prevention and control of T2DN, mechanistically understanding of the biofunction of FGF13 may also be of relevance to the pathogenesis of other FGF13- and Parkin-associated diseases.

Funding

This work was supported by the National Natural Science Foundation of China (82070507, 81900240, 81770498, 81773346), Zhejiang Provincial Natural Science Foundation of China (LZ21H020002), and the Natural Science Foundation of Ningbo (202003N4070).

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