title: Genetic depletion of glutathione peroxidase-1 potentiates nephrotoxicity induced by multiple doses of cocaine via activation of angiotensin II AT1 receptor.
abstract: 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.
authors.affiliation: a Neuropsychopharmacology and Toxicology Program, College of Pharmacy , Kangwon National University , Chunchon , Republic of Korea ;
authors.forename: Huynh Nhu
authors.initials: HN
authors.lastname: Mai
authors.affiliation: b Department of Anatomy, College of Medicine , Chung-Ang University, Seoul , Chunchon , Republic of Korea ;
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Chung
authors.affiliation: a Neuropsychopharmacology and Toxicology Program, College of Pharmacy , Kangwon National University , Chunchon , Republic of Korea ;
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Shin
authors.affiliation: c Department of Anatomy and Cell Biology, Medical School , Kangwon National University , Chunchon , Republic of Korea ;
authors.forename: Dae-Joong
authors.initials: DJ
authors.lastname: Kim
authors.affiliation: d Department of Pharmacology, College of Medicine , Chung-Ang University , Seoul , Republic of Korea ;
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: a Neuropsychopharmacology and Toxicology Program, College of Pharmacy , Kangwon National University , Chunchon , Republic of Korea ;
authors.forename: Thuy-Ty Lan
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: a Neuropsychopharmacology and Toxicology Program, College of Pharmacy , Kangwon National University , Chunchon , Republic of Korea ;
authors.forename: Yunsung
authors.initials: Y
authors.lastname: Nam
authors.affiliation: e Department of Clinical Pharmacy, College of Pharmacy , Kangwon National University , Chunchon , Republic of Korea ;
authors.forename: Yu Jeung
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: f Ginsentology Research Laboratory, Department of Physiology, College of Veterinary Medicine , Konkuk University , Seoul , Republic of Korea ;
authors.forename: Seung-Yeol
authors.initials: SY
authors.lastname: Nah
authors.affiliation: g Disease Model Research Laboratory, Aging Intervention Research Center , Korea Research Institute of Bioscience and Biotechnology (KRIBB) , Daejeon , Republic of Korea ;
authors.forename: Dae-Yeul
authors.initials: DY
authors.lastname: Yu
authors.affiliation: h Department of Pharmacology, School of Pharmacy , Sungkyunkwan University , Suwon , Republic of Korea ;
authors.forename: Choon-Gon
authors.initials: CG
authors.lastname: Jang
authors.affiliation: i Institute of Environmental Health Sciences , Wayne State University , Detroit , MI , USA ;
authors.forename: Ye-Shih
authors.initials: YS
authors.lastname: Ho
authors.affiliation: j Department of Animal Science , Cornell University , Ithaca , NY , USA.
authors.forename: Xin Gen
authors.initials: XG
authors.lastname: Lei
authors.affiliation: a Neuropsychopharmacology and Toxicology Program, College of Pharmacy , Kangwon National University , Chunchon , Republic of Korea ;
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
mesh_terms: D000818:Animals; D002867:Chromones / Q000494:pharmacology; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000235:genetics*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D050050:Protein Carbonylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013859:Thiocarbamates / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D002867:Chromones; D003042:Cocaine; D005978:Glutathione; D005979:Glutathione Peroxidase; D019808:Losartan; D008315:Malondialdehyde; D009025:Morpholines; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011759:Pyrrolidines; D044140:Receptor, Angiotensin, Type 1; D013859:Thiocarbamates; D051028:bcl-2-Associated X Protein; D000094765:Glutathione Peroxidase GPX1; C494827:Bax protein, mouse; C020972:pyrrolidine dithiocarbamic acid; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000722068:Gpx1 protein, mouse
keywords: AT1R; GPx-1 gene; PI3K/Akt signaling; cocaine; kidney; losartan