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 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.
['Mai|Huynh Nhu|HN|', 'Chung|Yoon Hee|YH|', 'Shin|Eun-Joo|EJ|', 'Kim|Dae-Joong|DJ|', 'Jeong|Ji Hoon|JH|', 'Nguyen|Thuy-Ty Lan|TT|', 'Nam|Yunsung|Y|', 'Lee|Yu Jeung|YJ|', 'Nah|Seung-Yeol|SY|', 'Yu|Dae-Yeul|DY|', 'Jang|Choon-Gon|CG|', 'Ho|Ye-Shih|YS|', 'Lei|Xin Gen|XG|', 'Kim|Hyoung-Chun|HC|']
D000818:Animals D002867:Chromones D003042:Cocaine D005260:Female D005786:Gene Expression Regulation D005978:Glutathione D005979:Glutathione Peroxidase D007668:Kidney D019808:Losartan D008297:Male D008315:Malondialdehyde D051379:Mice D018345:Mice, Knockout D009025:Morpholines D016328:NF-kappa B D010084:Oxidation-Reduction D018384:Oxidative Stress D019869:Phosphatidylinositol 3-Kinases D000081082:Phosphoinositide-3 Kinase Inhibitors D050050:Protein Carbonylation D047428:Protein Kinase Inhibitors D051057:Proto-Oncogene Proteins c-akt D011759:Pyrrolidines D044140:Receptor, Angiotensin, Type 1 D015398:Signal Transduction D013859:Thiocarbamates D051028:bcl-2-Associated X Protein
cocaine AT1R kidney losartan PI3K/Akt signaling GPx-1 gene