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

• Published in: Free radical research Vol. 50; no. 4; p. 467
• Main Authors: Mai, Huynh Nhu, Chung, Yoon Hee, Shin, Eun-Joo, Kim, Dae-Joong, Jeong, Ji Hoon, Nguyen, Thuy-Ty Lan, Nam, Yunsung, Lee, Yu Jeung, Nah, Seung-Yeol, Yu, Dae-Yeul, Jang, Choon-Gon, Ho, Ye-Shih, Lei, Xin Gen, Kim, Hyoung-Chun
• Format: Journal Article
• Language: English
• Published: England 02-04-2016
• Subjects: Animals; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Chromones - pharmacology; Cocaine - antagonists & inhibitors; Cocaine - toxicity; Female; Gene Expression Regulation; Glutathione - metabolism; Glutathione Peroxidase - deficiency; Glutathione Peroxidase - genetics; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Losartan - pharmacology; Male; Malondialdehyde - metabolism; Mice; Mice, Knockout; Morpholines - pharmacology; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; NF-kappa B - metabolism; Oxidation-Reduction; Oxidative Stress; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Protein Carbonylation - drug effects; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Pyrrolidines - pharmacology; Receptor, Angiotensin, Type 1 - genetics; Receptor, Angiotensin, Type 1 - metabolism; Signal Transduction; Thiocarbamates - pharmacology; kidney; PI3K/Akt signaling; AT1R; losartan; GPx-1 gene; cocaine
• ISSN: 1029-2470
• DOI: 10.3109/10715762.2016.1143097

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.