To CB2 or Not CB2: Revisiting Renoprotection in AKI and CKD

Cannabinoid receptor 2 (CBS) is a G-protein coupled receptor that controls immune responses and has recently emerged as a regulators of renal injury and repair. Over the past 15 years, numerous pharmacological and genetics studies have explored the role of CB2 in acute kidney injury (AKI) and chronic kidney disease (CKD). Using a wide array of chemical, metabolic, ischemia and obstructive mouse models, CB2 agonism has consistently preserved tubular epithelial cell integrity, reduced inflammation, and limited tubulointerstitial fibrosis. These protective effects were supported by the opposing outcomes in Cnr2 knockout mice, which showed worsened injury. More selective CB2 ligands with defined pharmacokinetic and pharmacodynamic profiles further reinforced the renoprotective role of CB2 agonism. In recent years, however, a small number of studies have suggested that CB2 may contribute to tubular damage, though there are issues of ligand selectivity, off-target activity, and methodological differences that complicate accurate interpretation. With this in mind, the prevailing evidence supports CB2 activation as beneficial in AKI and CKD and warrants continued progress to develop CB2 agonists for therapeutic applications for the kidney.