Cannabinoid receptor 2 activation is a novel approach to reducing renal inflammation and fibrosis

Authors

• B Yokus
• B Paes Leme Ferreira
• P Mukhopadhyay
• P Pacher

Abstract

Chronic kidney disease (CKD) culminates in renal fibrosis, a condition with limited treatments. Cannabinoid receptor 2 (CB2R) is a promising target for inflammatory disorders, with several selective agonists in clinical trials. This study examined CB2R’s localization in diseased kidneys and its role in kidney injury, inflammation, and fibrosis. We used pathology, biochemistry, molecular biology, pharmacology, and genetic approaches (knockout mice) to investigate CB2R in kidney injury induced by ischemia/reperfusion (I/R) or unilateral ureteral obstruction (UUO) in mice. Due to the lack of selective CB2R antibodies, advanced techniques like digital droplet PCR, RNA sequencing, and 3D high-resolution RNAscope were employed to explore CB2R localization and expression in normal and diseased kidneys, and isolated cell types. I/R and UUO models exhibited parenchyma injury, oxidative stress, inflammation, and fibrosis. Increased renal inflammation and fibrosis were associated with a rise in CB2R expression in damaged kidneys, originating from infiltrating immune cells (macrophages and lymphocytes) and activated fibroblasts, as shown by 3D RNAscope. Treatment with selective CB2R agonists (AM1241, HU910, RO6839828, RO6871304) significantly improved renal injury, inflammation, and fibrosis. Conversely, these conditions worsened with CB2R antagonists (XL-001, SR144528) or in CB2R knockout mice. Thus, CB2R is not expressed in normal kidneys, but its upregulation in kidney injury suggests an endogenous protective mechanism against injury and inflammation. Targeting CB2R in inflammatory cells with selective agonists may offer a novel treatment for acute and chronic kidney disease.

Scientific Focus Area: Molecular Pharmacology

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