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

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  • Liad Hinden

    (The Hebrew University of Jerusalem)

  • Majdoleen Ahmad

    (The Hebrew University of Jerusalem)

  • Sharleen Hamad

    (The Hebrew University of Jerusalem)

  • Alina Nemirovski

    (The Hebrew University of Jerusalem)

  • Gergő Szanda

    (Department of Physiology, Semmelweis University)

  • Sandra Glasmacher

    (University of Bern)

  • Aviram Kogot-Levin

    (Hadassah-Hebrew University Medical Center)

  • Rinat Abramovitch

    (Hadassah-Hebrew University Medical Center
    Hadassah-Hebrew University Medical Center)

  • Bernard Thorens

    (University of Lausanne)

  • Jürg Gertsch

    (University of Bern)

  • Gil Leibowitz

    (Hadassah-Hebrew University Medical Center)

  • Joseph Tam

    (The Hebrew University of Jerusalem)

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.

Suggested Citation

  • Liad Hinden & Majdoleen Ahmad & Sharleen Hamad & Alina Nemirovski & Gergő Szanda & Sandra Glasmacher & Aviram Kogot-Levin & Rinat Abramovitch & Bernard Thorens & Jürg Gertsch & Gil Leibowitz & Joseph , 2022. "Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29124-8
    DOI: 10.1038/s41467-022-29124-8
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    References listed on IDEAS

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    1. Ruth Milkereit & Avinash Persaud & Liviu Vanoaica & Adriano Guetg & Francois Verrey & Daniela Rotin, 2015. "LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
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