Fatty acid amide hydrolase inhibition impairing development of chronic renal fibrosis is CB2R dependent

Authors

• B Paes-Leme
• E Trojanar
• C Matyas
• B Yokus
• P Mukhopadhyay
• M Arif
• J Paloczi
• R Cinar
• K Susztak
• S Zhao
• P Pacher

Abstract

Renal fibrosis, marked by an abnormal buildup and deposition of extracellular matrix components, represents the ultimate outcome of chronic kidney disease with limited available treatment options. Emerging evidence indicates the involvement of the endocannabinoid system comprising of cannabinoid 1 and 2 receptors (CB1R/CB2R), their endogenous ligands anandamide and 2-diacylglycerol, and metabolic enzymes in both inflammatory and fibrotic processes. In this study, using biochemical analyses, pathology examinations, and molecular biology techniques, we explored the role of the fatty acid amide hydrolase (FAAH), the enzyme responsible for the anandamide metabolism, in kidney inflammation and fibrosis induced by unilateral ureteral obstruction (UUO) in mice. UUO induced massive general and vascular inflammation, oxidative/nitrative stress, parenchyma loss, and fibrotic remodeling in the kidney one week following the surgery. These changes were accompanied by increased renal FAAH activity and decreased anandamide levels. Inhibition of FAAH with FDA-approved inhibitor PF-04457845 or genetic deletion of the enzyme lead to attenuation of such deleterious effects. Recent studies have demonstrated anti-inflammatory/fibrotic effects of CB2R primarily expressed in immune cells in models of kidney inflammation/fibrosis. Consistent with the beneficial effects of CB2R activation in kidney injury, we found that in CB2R knockout mice subjected to UUO the protective effects of the FAAH inhibitor PF-04457845 were largely abolished. Collectively, our data indicates that the protective endocannabinoid-CB2R signaling is impaired during kidney injury, which could be restored by FAAH inhibition. Furthermore, we provide evidence that FAAH inhibition represents a promising novel approach for the treatment of chronic kidney disease.

Scientific Focus Area: Molecular Pharmacology

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