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

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 m...

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Published in:Free radical research 2016-04, Vol.50 (4), p.467-483
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: Article
Language:English
Subjects:
Animals
AT1R
bcl-2-Associated X Protein - genetics
bcl-2-Associated X Protein - metabolism
Chromones - pharmacology
cocaine
Cocaine - antagonists & inhibitors
Cocaine - toxicity
Female
Gene Expression Regulation
Glutathione - metabolism
Glutathione Peroxidase - deficiency
Glutathione Peroxidase - genetics
GPx-1 gene
kidney
Kidney - drug effects
Kidney - metabolism
Kidney - pathology
losartan
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
PI3K/Akt signaling
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
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Summary: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.
ISSN:1071-5762
1029-2470
DOI:10.3109/10715762.2016.1143097