4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41467-022-29124-8

Keywords

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Funding

  1. ERC-2015-StG grant [676841]
  2. Israel Science Foundation (ISF) [158/18]
  3. JDRF grant [1-INO-2022-1128-A-N]
  4. National Research, Development and Innovation Office [NKFI-6/FK_124038]

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This study reveals that the activation of cannabinoid-1 receptor (CB1R) and mammalian target of rapamycin complex 1 (mTORC1) in renal proximal tubular cells (RPTCs) is involved in the development of diabetic kidney disease (DKD). Stimulation of endocannabinoid/CB1R by hyperglycemia increases mTORC1 activity and promotes the transcription of facilitative glucose transporter 2 (GLUT2), leading to DKD in mice. Conversely, CB1R maintains the normal activity of mTORC1 by preventing amino acid uptake during normoglycemia. This finding highlights the importance of the CB1/mTORC1/GLUT2 signaling axis in regulating nutrient homeostasis in healthy and diseased kidneys.
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. Renal proximal tubules modulate whole-body homeostasis by sensing various nutrients. Here the authors describe the existence and importance of a unique CB1/mTORC1/GLUT2 signaling axis in regulating nutrient homeostasis in healthy and diseased kidney.

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