Cannabinoid receptor 1 is a major mediator of renal fibrosis

Lola Lecru, Christophe Desterke, Stanislas Grassin-Delyle, Christos Chatziantoniou, Sophie Vandermeersch, Aurore Devocelle, Amelia Vernochet, Ninoslav Ivanovski, Catherine Ledent, Sophie Ferlicot, Meriem Dalia, Myriam Saïd, Séverine Beaudreuil, Bernard Charpentier, Aimé Vazquez, Julien Giron-Michel, Bruno Azzarone, Antoine Durrbach, Hélène François

Research output: Contribution to journalArticle

Abstract

Chronic kidney disease, secondary to renal fibrogenesis, is a burden on public health. There is a need to explore new therapeutic pathways to reduce renal fibrogenesis. To study this, we used unilateral ureteral obstruction (UUO) in mice as an experimental model of renal fibrosis and microarray analysis to compare gene expression in fibrotic and normal kidneys. The cannabinoid receptor 1 (CB1) was among the most upregulated genes in mice, and the main endogenous CB1 ligand (2-arachidonoylglycerol) was significantly increased in the fibrotic kidney. Interestingly, CB1 expression was highly increased in kidney biopsies of patients with IgA nephropathy, diabetes, and acute interstitial nephritis. Both genetic and pharmacological knockout of CB1 induced a profound reduction in renal fibrosis during UUO. While CB2 is also involved in renal fibrogenesis, it did not potentiate the role of CB1. CB1 expression was significantly increased in myofibroblasts, the main effector cells in renal fibrogenesis, upon TGF-β1 stimulation. The decrease in renal fibrosis during CB1 blockade could be explained by a direct action on myofibroblasts. CB1 blockade reduced collagen expression in vitro. Rimonabant, a selective CB1 endocannabinoid receptor antagonist, modulated the macrophage infiltrate responsible for renal fibrosis in UUO through a decrease in monocyte chemoattractant protein-1 synthesis. Thus, CB1 has a major role in the activation of myofibroblasts and may be a new target for treating chronic kidney disease.

Original languageEnglish
Pages (from-to)72-84
Number of pages13
JournalKidney International
Volume88
Issue number1
DOIs
Publication statusPublished - Jul 2 2015

Keywords

  • Cannabinoid
  • Chronic kidney disease
  • Fibrosis
  • Myofibroblast

ASJC Scopus subject areas

  • Nephrology

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  • Cite this

    Lecru, L., Desterke, C., Grassin-Delyle, S., Chatziantoniou, C., Vandermeersch, S., Devocelle, A., Vernochet, A., Ivanovski, N., Ledent, C., Ferlicot, S., Dalia, M., Saïd, M., Beaudreuil, S., Charpentier, B., Vazquez, A., Giron-Michel, J., Azzarone, B., Durrbach, A., & François, H. (2015). Cannabinoid receptor 1 is a major mediator of renal fibrosis. Kidney International, 88(1), 72-84. https://doi.org/10.1038/ki.2015.63