FC024: Renal Proximal Tubules CB1 Receptor Modulates MTORC1 Signalling in Health and Disease. (3rd May 2022)

• Record Type: Journal Article
• Authors: Hinden, Liad; Ahmad, Majdoleen; Hamad, Sharleen; Nemirovski, Alina; Glasmacher, Sandra; Kogot-Levin, Aviram; Gertsch, Jürg; Leibowitz, Gil; Tam, Joseph
• Is Part Of: Nephrology dialysis transplantation. Volume 37(2022)Supplement 3
• Publication Date: 2022-05-03
• Subjects: Nephrology -- Periodicals; Hemodialysis -- Periodicals; Kidneys -- Transplantation -- Periodicals; Hemodialysis; Kidneys -- Transplantation; Nephrology; Periodicals; 616.61
• DOI: 10.1093/ndt/gfac099.003
• Languages: English
• ISSNs: 0931-0509

Abstract

Abstract: BACKGROUND AND AIMS: Diabetic kidney disease (DKD), the renal manifestation of diabetes, contributes to increased morbidity and mortality of patients with diabetes. Activation of the cannabinoid-1 receptor (CB1 R) and the mammalian target of rapamycin complex 1 (mTORC1) in the renal proximal tubular cells (RPTCs) contributes to the development of DKD. However, whether these two signalling molecules interact with each other to regulate kidney function during health and disease has not been described yet. METHOD: By using a multidisciplinary approach that includes pharmacological and genetic manipulations of CB1 R and mTORC1, we assessed the effect of CB1 R activation/inhibition on mTORC1 activity under conditions of acute and chronic hyperglycaemia or normoglycaemia in RPTCs and mice. RESULTS: We showed hyperglycaemia-induced endocannabinoid/CB1 R stimulation. This stimulation increased mTORC1 activity and resulted in enhancing the expression of sterol regulatory element-binding protein 1c (SREBP1c) and its nuclear translocation, which in turn, induced the transcription of the facilitative glucose transporter 2 (GLUT2), thus leading to the development of DKD in mice. This effect was ameliorated by CB1 R or mTORC1 nullification specifically in RPTCs. However, in non-diabetic conditions, CB1 R maintained normal activation of mTORC1 by preventing the cellular excess of various amino acids via regulating their transporters, megalin, SLC6A19 and SLC7A5. CONCLUSION: Our findings highlight two novel molecular mechanisms by which the activation of mTORC1 in RPTCs is tightly controlled by CB1 R, either by enhancing the reabsorption of glucose and inducing renal dysfunction in diabetes or by preventing amino acid uptake and maintaining normal kidney function in healthy conditions. Moreover, this work highlights the therapeutic potential of targeting peripheral CB1 Rs for the treatment of DKD, and on the other hand, avoiding its use in non-diabetic patients due to their possible effect on enhancing mTORC1 signalling.