Downregulation of the kidney glucagon receptor, essential for renal function and systemic homeostasis, contributes to chronic kidney disease

The glucagon receptor (GCGR) in the kidney is expressed in nephron tubules. In humans and animal models with chronic kidney disease, renal GCGR expression is reduced. However, the role of kidney GCGR in normal renal function and in disease development has not been addressed. Here, we examined its role by analyzing mice with constitutive or conditional kidney-specific loss of the Gcgr. Adult renal Gcgr knockout mice exhibit metabolic dysregulation and a functional impairment of the kidneys. These mice exhibit hyperaminoacidemia associated with reduced kidney glucose output, oxidative stress, enhanced inflammasome activity, and excess lipid accumulation in the kidney. Upon a lipid challenge, they display maladaptive responses with acute hypertriglyceridemia and chronic proinflammatory and profibrotic activation. In aged mice, kidney Gcgr ablation elicits widespread renal deposition of collagen and fibronectin, indicative of fibrosis. Taken together, our findings demonstrate an essential role of the renal GCGR in normal kidney metabolic and homeostatic functions. Importantly, mice deficient for kidney Gcgr recapitulate some of the key pathophysiological features of chronic kidney disease. [Display omitted] •Kidney GCGR deficiency causes hyperaminoacidemia with reduced renal glucose output•Kidney GCGR deficiency promotes renal lipid deposition, inflammation, and fibrosis•Kidney GCGR deficiency induces systemic nitrogen, water, and electrolyte imbalances•Kidney GCGR deficiency elicits hypertension Wang et al. show that kidney glucagon receptor (GCGR)-deficient mice exhibit renal metabolic anomalies and homeostatic dysfunctions. These mice recapitulate several features of human chronic kidney disease (CKD), often associated with attenuated renal GCGR. Their study thus highlights a likely causative role of GCGR downregulation in the development of CKD.