Synthetic Cannabinoids JWH-122 and THJ-2201 Disrupt Endocannabinoid-Regulated Mitochondrial Function and Activate Apoptotic Pathways as a Primary Mechanism of In Vitro Nephrotoxicity at In Vivo Relevant Concentrations.

摘要: The widespread recreational use of synthetic cannabinoids (SCBs) represents a major public health issue, as reports intoxications and deaths following SCB rapidly mount up. Specifically, direct link between acute kidney injury (AKI) has been established, although the pathophysiologic mechanisms remain undefined. Here we assessed in vitro nephrotoxicity 3 commonly detected structurally distinct SCBs-AB-FUBINACA, JWH-122, THJ-2201-in human proximal tubule cells (HK-2), to ascertain potential similarities and/or differences regarding their signatures. We showed that 2 SCBs tested, namely JWH-122 THJ-2201, at vivo relevant concentrations (1 nM-1 μM), triggered apoptotic cell death pathways, mainly through shared mechanism involving deregulation mitochondrial function (ie, with membrane hyperpolarization increased intracellular ATP levels), primary molecular signature mechanism. Noteworthy, no affected viability (MTT reduction, lactate dehydrogenase release, Neutral Red inclusion). Use cannabinoid receptor (CBR) antagonists SR141716A SR144528, well HEK293T cells, which do not express CBRs, confirmed involvement these receptors SCB-mediated but on other events, suggesting an off-target action regulating SCB-induced death. Our results further strengthen relevance endocannabinoid system maintaining demonstrate HK-2 incubation CBR or inhibitors biosynthesis methyl arachydonyl fluorophosphonate, tetrahydrolipstatin) alone produced deleterious effects similar those now reported for SCBs. Overall, seems be regulated level, specific involved require clarification.