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

Liad Hinden1, Majdoleen Ahmad1, Sharleen Hamad1

  • 1Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.

Nature Communications
|April 5, 2022
PubMed

Insights

Cannabinoid receptor 1 (CB1R) and mTORC1 signaling in kidney cells drive diabetic kidney disease by increasing glucose transporter 2 (GLUT2). CB1R also protects kidneys in healthy states by regulating amino acids.

Area of Science:

  • Nephrology
  • Endocrinology
  • Molecular Biology

Background:

  • Diabetic kidney disease (DKD) involves cannabinoid-1 receptor (CB1R) and mammalian target of rapamycin complex 1 (mTORC1) in renal proximal tubular cells (RPTCs).
  • The specific interplay between CB1R and mTORC1 in the kidney remains uncharacterized.

Purpose of the Study:

  • To elucidate the CB1R/mTORC1 signaling axis in renal proximal tubular cells (RPTCs).
  • To investigate the role of this axis in the development and regulation of diabetic kidney disease (DKD).

Main Methods:

  • Utilized mouse models of diabetic kidney disease.
  • Investigated the effects of hyperglycemia on endocannabinoid/CB1R stimulation and mTORC1 activity.
  • Examined the role of glucose transporter 2 (GLUT2) in RPTCs via gene ablation.

Main Results:

  • Hyperglycemia-induced CB1R activation increased mTORC1 activity and GLUT2 transcription, contributing to DKD.
  • Ablation of GLUT2 in RPTCs ameliorated DKD development.
  • CB1R prevented excessive amino acid uptake, maintaining normal mTORC1 activity and kidney function under normoglycemia.

Conclusions:

  • CB1R tightly regulates mTORC1 activation in RPTCs.
  • In diabetes, CB1R activation promotes glucose reabsorption via GLUT2, leading to kidney dysfunction.
  • In healthy conditions, CB1R prevents amino acid excess, preserving normal kidney function.

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