Prolonged Glucagon Exposure Rewires Lipid Oxidation and Drives Diabetic Kidney Disease Progression

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD), and few treatment options are available today to prevent the progressive loss of renal function. Tubular abnormalities may precede glomerular pathology early and indicate the functional progression of DKD, however, pathological mechanisms that initiate tubular abnormalities are poorly understood. Here, we found that glucagon receptor (Gcgr) is specifically and highly expressed in proximal tubular cells (PTEC) of kidney. Glucagon injection exacerbated lipid accumulation, glycogen content, inflammation, fibrosis, and renal injury, along with morphology changes on proximal tubules, podocytes, glomerular basement membrane (GBM), and mitochondria in the early phase of DKD mice. Whereas, the specific knockdown or knockout of Gcgr in PTEC of kidney almost completely halted the development of DKD. In contrary to the effect of short-term glucagon stimulation on fatty acid oxidation, long-term glucagon exposure led to glucagon reversal in PTEC, which is characterized by reduced energy production and promoted lipogenesis, and this effect was through the Gcgr-PKA-Creb-mTOR pathway. Accordingly, anti-GCGR antibody treatment greatly blocked the pathogenesis of DKD induced by both type 2 and type 1 diabetes. Thus, our results revealed a novel role of glucagon/GCGR signaling in PTEC lipogenesis and DKD, and Gcgr would be a promising therapeutic drug target for the treatment of DKD.