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

Abstract

<p>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 <em>Fgf13</em> potentially alleviates T2DN damage, while<em> Fgf13 </em>overexpression has the opposite effects. Mechanistically, <em>Fgf13 </em>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 <em>Fgf13</em> deficiency on T2DN are abolished by endothelial-specific double deletion of <em>Fgf13</em> and <em>Prkn</em>. The effects of <em>Fgf13</em> 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 <em>Fgf13</em> 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.</p>