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

Autor: Hyoung-Chun Kim, Dae-Joong Kim, Xin Gen Lei, Yoon Hee Chung, Seung Yeol Nah, Huynh Nhu Mai, Yu Jeung Lee, Ye-Shih Ho, Dae Yeul Yu, Eun-Joo Shin, Choon-Gon Jang, Yunsung Nam, Ji Hoon Jeong, Thuy Ty Lan Nguyen
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
GPX1
Pyrrolidines
Pharmacology
Kidney
Biochemistry
Protein Carbonylation
Mice
Phosphatidylinositol 3-Kinases
Glutathione Peroxidase GPX1
0302 clinical medicine
Cocaine
Malondialdehyde
Phosphoinositide-3 Kinase Inhibitors
bcl-2-Associated X Protein
Mice
Knockout
chemistry.chemical_classification
Glutathione peroxidase
NF-kappa B
General Medicine
Glutathione
medicine.anatomical_structure
Losartan
Toxicity
Female
Oxidation-Reduction
Signal Transduction
medicine.drug
medicine.medical_specialty
Morpholines
Receptor
Angiotensin
Type 1
Nephrotoxicity
03 medical and health sciences
Thiocarbamates
Internal medicine
medicine
Animals
Protein Kinase Inhibitors
Glutathione Peroxidase
Angiotensin II receptor type 1
Angiotensin II
Oxidative Stress
030104 developmental biology
Endocrinology
Gene Expression Regulation
chemistry
Chromones
Proto-Oncogene Proteins c-akt
030217 neurology & neurosurgery
Zdroj: Free Radical Research. 50:467-483
ISSN: 1029-2470
1071-5762
Popis: 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.
Databáze: OpenAIRE
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