Genetic depletion of glutathione peroxidase-1 potentiates nephrotoxicity induced by multiple doses of cocaine via activation of angiotensin II AT1 receptor

ABSTRACT

We investigated the possible roles of angiotensin II type 1 receptor (AT1R) and oxidative stress responsive nuclear factor κB (NFκB) in renal damage caused by multiple doses of cocaine in glutathione peroxidase (GPx)-1 gene-depleted mice. Treatment with cocaine resulted in significant increases in malondialdehyde, protein carbonyl, and pro-apoptotic Bax expression and decreases in the ratio of glutathione (GSH) and its oxidized form (GSSG), GSH-dependent enzymes, and anti-apoptotic factors in the kidney. These alterations were more pronounced in GPx-1 knockout (−/−) mice than in wild type (WT) mice. Notably, the AT1R antagonist losartan protected against the renal toxicity induced by cocaine, whereas the NFκB inhibitor pyrrolidine dithiocarbamate was not protective. The toxicity was more pronounced in GPx-1 (−/−) mice than in WT mice. The protective effect afforded by losartan against cocaine toxicity appeared to be more sensitive in GPx-1 (−/−) mice than that in WT mice. These losartan-mediated protective effects were inhibited by the phosphatidyl-inositol-3-kinase (PI3K) inhibitor LY294002, indicating that losartan provides significant protection from cocaine-induced renal toxicity through PI3K/Akt signaling. Our results suggest that genetic inhibition of GPx-1 potentiates cocaine-induced renal damage via activation of AT1R by inhibition of PI3K-Akt signaling, and that AT1R can be a therapeutic target against renal toxicity induced by cocaine.

KEYWORDS:

• AT1R
• cocaine
• GPx-1 gene
• kidney
• losartan
• PI3K/Akt signaling

Acknowledgements

Equipment at the Institute of New Drug Development Research (Kangwon National University) was used for this study. The English in this document has been checked by at least two professional editors, both native speakers of English.

Disclosure statement

The authors declare that they have no conflict of interest.

Funding information

This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration. Yunsung Nam, Thuy-Ty Lan Nguyen and Huynh Nhu Mai were supported by the BK21 PLUS program, National Research Foundation of Korea, Republic of Korea.

Ethical Approval: All procedures performed in studies involving animals were in strict accordance with the ethical standards of the Kangwon National University IACUC and the NIH Guide for the Humane Care and Use of Laboratory Animals. This article does not contain any studies with human participants performed by any of the authors.