Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease with limited therapeutic options. Although dysfunction of podocytes has been proved to critically associated with DKD, the mechanism underlying remains unclear. Here we identify mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) as a critical regulator of podocyte function during diabetic conditions. Specifically, its expressions were significantly decreased in the glomerular of diabetic mice, and it co-expressed with podocyte marker-WT1. By generating podocyte-specific mGPDH KO mice via breeding mGPDHfl/fl with podocin-Cre mice, we found significant higher levels of albuminuria in KO mice compared to WT during diabetes. Histological analysis showed greater mesangial expansion and decreased WT1 expressions in KO mice with diabetes. In keeping with this, the expressions of renal fibrosis genes were increased and mitochondrial contents and OXPHOS functions were decreased in KO mice with diabetes (Figure 1). Further molecular mechanism exploration showed that mGPDH regulates podocyte function might through AGEs/RAGE pathway. Rescuing mGPDH in STZ mice via AAV led to a significant improvement in their glomerular pathology and renal function. Our findings suggest that targeting mGPDH may be beneficial to attenuate diabetes-induced podocyte dysfunction and kidney injury.
H. Qu: None. Y. Zheng: None.
