The synthetic cannabinoid XLR-11 induces in vitro nephrotoxicity by impairment of endocannabinoid-mediated regulation of mitochondrial function homeostasis and triggering of apoptosis

We demonstrate that XLR-11, at biologically relevant concentrations (in the nanomolar range), primarily targets mitochondrial function in human proximal tubule (HK-2) cells, inducing a transient hyperpolarization of the mitochondrial membrane and increasing ATP production, accompanied by Bax translocation from cytosol into mitochondria. These phenomena further triggered energy-dependent apoptotic cell death pathways, indicated by increased caspase-3 activity and chromatin condensation. Experiments using SR141716A and SR144258, specific antagonists for CB1 and CB2 receptors, respectively, as well as HEK293T cells (which do not express CBRs) highlighted these processes' dependence on CBR activation. Nevertheless, ATP formation seemed to follow a CBR-independent pathway. Our findings using specific inhibitors of endogenous cannabinoids biosynthesis (i.e. MAFP and THL) further evidenced the involvement of the endocannabinoid system in the regulation of these processes, as XLR-11 binding to CBRs seemed to compromise endocannabinoid-mediated preservation of mitochondrial function. Nevertheless, the exact mechanisms involved require further clarification.