To CB2 or not CB2: Revisiting renoprotection in acute and chronic kidney injury

The cannabinoid receptor 2 (CB2), which is encoded by the Cnr2 gene, is a G-protein-coupled receptor that controls immune responses and has recently emerged as a regulator 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). Although the precise localisation of CB2 within renal compartments remains under debate, pharmacologically mediated CB2 agonism, across a wide array of chemical, metabolic, ischaemia and obstructive mouse models, has consistently preserved tubular epithelial cell integrity, reduced inflammation, and limited tubulointerstitial fibrosis. These protective effects of CB2 activation are further supported by the opposing outcomes in Cnr2 knockout mice, which showed worsened injury. More selective CB2 ligands with defined pharmacokinetic and pharmacodynamic profiles in preclinical animal models along with late-stage clinical studies have further substantiated the safety and efficacy of this type of therapeutic approach. Nevertheless, a few studies have reported conflicting results, suggesting a CB2-dependent contribution towards tubular damage, although these findings are complicated by differences in ligand selectivity, possible off-target activity, and experimental design. With this in mind, the prevailing evidence supports CB2 activation as beneficial in both AKI and CKD and warrants continued translational progress to develop CB2 agonists for therapeutic applications in kidney disease.