Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function

Activation of the cannabinoid-1 receptor (CB(1)R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of diabetic kidney disease (DKD). However, the CB(1)R/mTORC1 signaling axis in the kidney has not been described yet. We show here that hyperglycemia-induced endocannabinoid/CB(1)R stimulation increased mTORC1 activity, enhancing the transcription of the facilitative glucose transporter 2 (GLUT2) and leading to the development of DKD in mice; this effect was ameliorated by specific RPTCs ablation of GLUT2. Conversely, CB(1)R maintained the normal activity of mTORC1 by preventing the cellular excess of amino acids during normoglycemia. Our findings highlight a novel molecular mechanism by which the activation of mTORC1 in RPTCs is tightly controlled by CB(1)R, either by enhancing the reabsorption of glucose and inducing kidney dysfunction in diabetes or by preventing amino acid uptake and maintaining normal kidney function in healthy conditions.