title: Cannabinoid receptor 1 is a major mediator of renal fibrosis.
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.
authors.affiliation: INSERM Unité 1014, Régulation de la survie et des Allogreffes, Institut André Lwoff, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Lola
authors.initials: L
authors.lastname: Lecru
authors.affiliation: INSERM Unité 972, Transfert des gènes dans le foie: Applications Thérapeutiques, Institut André Lwoff, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Desterke
authors.affiliation: Université de Versailles Saint-Quentin, Mass Spectrometry Facility, MasSpecLab, Versailles, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Grassin-Delyle
authors.affiliation: UMRS 702, Remodelage et Réparation du Tissu Rénal, Hôpital Tenon, Paris, France.
authors.forename: Christos
authors.initials: C
authors.lastname: Chatziantoniou
authors.affiliation: UMRS 702, Remodelage et Réparation du Tissu Rénal, Hôpital Tenon, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vandermeersch
authors.affiliation: INSERM Unité 1014, Régulation de la survie et des Allogreffes, Institut André Lwoff, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Devocelle
authors.affiliation: INSERM Unité 1014, Régulation de la survie et des Allogreffes, Institut André Lwoff, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Amelia
authors.initials: A
authors.lastname: Vernochet
authors.affiliation: INSERM Unité 1014, Régulation de la survie et des Allogreffes, Institut André Lwoff, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Ninoslav
authors.initials: N
authors.lastname: Ivanovski
authors.affiliation: Institut de la Recherche Interdisciplinaire en Biologie Humaine Et Moléculaire, Bruxelles, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.affiliation: AP-HP Hôpital Bicêtre, le Kremlin-Bicêtre, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Ferlicot
authors.affiliation: INSERM Unité 1014, Régulation de la survie et des Allogreffes, Institut André Lwoff, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Meriem
authors.initials: M
authors.lastname: Dalia
authors.affiliation: INSERM Unité 1014, Régulation de la survie et des Allogreffes, Institut André Lwoff, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Saïd
authors.affiliation: 1] INSERM Unité 1014, Régulation de la survie et des Allogreffes, Institut André Lwoff, Hôpital Paul Brousse, Villejuif, France [2] AP-HP Hôpital Bicêtre, le Kremlin-Bicêtre, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Beaudreuil
authors.affiliation: 1] INSERM Unité 1014, Régulation de la survie et des Allogreffes, Institut André Lwoff, Hôpital Paul Brousse, Villejuif, France [2] AP-HP Hôpital Bicêtre, le Kremlin-Bicêtre, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Charpentier
authors.affiliation: INSERM Unité 1014, Régulation de la survie et des Allogreffes, Institut André Lwoff, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Aimé
authors.initials: A
authors.lastname: Vazquez
authors.affiliation: INSERM Unité 1014, Régulation de la survie et des Allogreffes, Institut André Lwoff, Hôpital Paul Brousse, Villejuif, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Giron-Michel
authors.affiliation: Immunology Department, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Azzarone
authors.affiliation: 1] INSERM Unité 1014, Régulation de la survie et des Allogreffes, Institut André Lwoff, Hôpital Paul Brousse, Villejuif, France [2] AP-HP Hôpital Bicêtre, le Kremlin-Bicêtre, France [3] Institut Francilien de Recherche en Néphrologie et Transplantation, le Kremlin-Bicêtre, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Durrbach
authors.affiliation: 1] INSERM Unité 1014, Régulation de la survie et des Allogreffes, Institut André Lwoff, Hôpital Paul Brousse, Villejuif, France [2] AP-HP Hôpital Bicêtre, le Kremlin-Bicêtre, France [3] Institut Francilien de Recherche en Néphrologie et Transplantation, le Kremlin-Bicêtre, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: François
mesh_terms: D000208:Acute Disease; D000818:Animals; D001095:Arachidonic Acids; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism; D004195:Disease Models, Animal; D063388:Endocannabinoids; D005355:Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005922:Glomerulonephritis, IGA / Q000378:metabolism; D005989:Glycerides; D006801:Humans; D007668:Kidney / Q000473:pathology*; D008024:Ligands; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism*; D009395:Nephritis, Interstitial / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000032:analysis / Q000235:genetics*; D043885:Receptor, Cannabinoid, CB2 / Q000032:analysis / Q000235:genetics; D000077285:Rimonabant; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000150:complications / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D063388:Endocannabinoids; D005989:Glycerides; D008024:Ligands; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D053773:Transforming Growth Factor beta1; C094503:glyceryl 2-arachidonate; D003094:Collagen; D000077285:Rimonabant