Nat Commun. 2022 Apr 4;13(1):1783. doi: 10.1038/s41467-022-29124-8.

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

Liad Hinden ¹, Majdoleen Ahmad ¹, Sharleen Hamad ¹, Alina Nemirovski ¹, Gergő Szanda ², Sandra Glasmacher ³, Aviram Kogot-Levin ⁴, Rinat Abramovitch ^5 6, Bernard Thorens ⁷, Jürg Gertsch ³, Gil Leibowitz ⁴, Joseph Tam ⁸

Abstract

Activation of the cannabinoid-1 receptor (CB₁R) 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 CB₁R/mTORC1 signaling axis in the kidney has not been described yet. We show here that hyperglycemia-induced endocannabinoid/CB₁R 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, CB₁R 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 CB₁R, 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.

• PMID: 35379807
• DOI: 10.1038/s41467-022-29124-8