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 |
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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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