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

• Type: Article in International Scientific Journal
• Date: 2019

Authors

João Silva (Author) FFUP; Ana Margarida Araújo (Author) Other; Paula Guedes de Pinho (Author) FFUP; Helena Carmo (Author) FFUP; Felix Carvalho (Author) FFUP

Journal

Title: Toxicological Sciences

Vol. 169

Pages: 422-435

ISSN: 1096-6080

Publisher: Oxford University Press

Indexing

ISI Web of Knowledge - 15 Citations

Scopus - 17 Citations

Associated Projects

NEUROSCANN - NEUROSCANN - Avaliação dos efeitos moduladores de canabinóides sintéticos sobre desenvolvimento neuronal

Other information

Authenticus ID: P-00Q-QHN

DOI: 10.1093/toxsci/kfz050

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

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 14