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

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.

SUBMITTER: Hinden L

PROVIDER: S-EPMC8980033 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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

Hinden Liad L Ahmad Majdoleen M Hamad Sharleen S Nemirovski Alina A Szanda Gergő G Glasmacher Sandra S Kogot-Levin Aviram A Abramovitch Rinat R Thorens Bernard B Gertsch Jürg J Leibowitz Gil G Tam Joseph J

Nature communications 20220404 1

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 ( ...[more]

PMID: 35379807

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Dataset Information

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

Publications

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

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