title: Nebivolol prevents ethanol-induced reactive oxygen species generation and lipoperoxidation in the rat kidney by regulating NADPH oxidase activation and expression.
abstract: We studied whether the β1-adrenergic antagonist nebivolol would prevent ethanol-induced reactive oxygen species generation and lipoperoxidation in the rat renal cortex. Male Wistar rats were treated with ethanol (20% v/v) for 2 weeks. Nebivolol (10mg/kg/day; p.o. gavage) prevented both the increase in superoxide anion (O2-) generation and thiobarbituric acid reactive substances (TBARS) concentration induced by ethanol in the renal cortex. Ethanol decreased nitrate/nitrite (NOx) concentration in the renal cortex, and nebivolol prevented this response. Nebivolol did not affect the reduction of hydrogen peroxide (H2O2) concentration induced by ethanol. Nebivolol prevented the ethanol-induced increase of catalase (CAT) activity. Both SOD activity and the levels of reduced glutathione (GSH) were not affected by treatment with nebivolol or ethanol. Neither ethanol nor nebivolol affected the expression of Nox1, Nox4, eNOS, nNOS, CAT, Nox organizer 1 (Noxo1), c-Src, p47phoxor superoxide dismutase (SOD) isoforms in the renal cortex. On the other hand, treatment with ethanol increased Nox2 expression, and nebivolol prevented this response. Finally, nebivolol reduced the expression of protein kinase (PK) Cδ and Rac1. The major finding of our study is that nebivolol prevented ethanol-induced reactive oxygen species generation and lipoperoxidation in the kidney by a mechanism that involves reduction on the expression of Nox2, a catalytic subunit of NADPH oxidase. Additionally, we demonstrated that nebivolol reduces NADPH oxidase-derived reactive oxygen species by decreasing the expression of PKCδ and Rac1, which are important activators of NADPH oxidase.
authors.affiliation: Programa de pós-graduação em Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil; Laboratório de Farmacologia, DEPCH, Escola de Enfermagem de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Gabriel T
authors.initials: GT
authors.lastname: do Vale
authors.affiliation: Programa de pós-graduação em Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil; Laboratório de Farmacologia, DEPCH, Escola de Enfermagem de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Natália A
authors.initials: NA
authors.lastname: Gonzaga
authors.affiliation: Programa de pós-graduação em Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, São Paulo, Brazil; Laboratório de Farmacologia, DEPCH, Escola de Enfermagem de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Janaina A
authors.initials: JA
authors.lastname: Simplicio
authors.affiliation: Laboratório de Farmacologia, DEPCH, Escola de Enfermagem de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil. Electronic address: crtirapelli@eerp.usp.br.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Tirapelli
mesh_terms: D000818:Animals; D003404:Creatinine / Q000097:blood; D019610:Cytoprotection / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D000068577:Nebivolol / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011188:Potassium / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012964:Sodium / Q000097:blood; D013481:Superoxides / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D009589:Nitrogen Oxides; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D000068577:Nebivolol; D013481:Superoxides; D000431:Ethanol; D012964:Sodium; D003404:Creatinine; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D011188:Potassium
keywords: Ethanol; NADPH oxidase; Nebivolol; Oxidative stress; Superoxide anion