Cannabinoid receptor 1 is a major mediator of renal fibrosis

Kidney Int. 2015 Jul;88(1):72-84. doi: 10.1038/ki.2015.63. Epub 2015 Mar 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Arachidonic Acids
  • Cells, Cultured
  • Chemokine CCL2 / metabolism
  • Collagen / metabolism
  • Diabetes Mellitus / metabolism
  • Disease Models, Animal
  • Endocannabinoids
  • Fibrosis / genetics*
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Gene Expression Profiling
  • Glomerulonephritis, IGA / metabolism
  • Glycerides
  • Humans
  • Kidney / pathology*
  • Ligands
  • Macrophages / drug effects
  • Mice
  • Mice, Knockout
  • Myofibroblasts / drug effects
  • Myofibroblasts / metabolism*
  • Nephritis, Interstitial / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • RNA, Messenger / metabolism*
  • Receptor, Cannabinoid, CB1 / analysis
  • Receptor, Cannabinoid, CB1 / genetics*
  • Receptor, Cannabinoid, CB2 / analysis
  • Receptor, Cannabinoid, CB2 / genetics
  • Rimonabant
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / metabolism
  • Up-Regulation
  • Ureteral Obstruction / complications
  • Ureteral Obstruction / metabolism


  • Arachidonic Acids
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Endocannabinoids
  • Glycerides
  • Ligands
  • Piperidines
  • Pyrazoles
  • RNA, Messenger
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Transforming Growth Factor beta1
  • glyceryl 2-arachidonate
  • Collagen
  • Rimonabant