do Vale Gabriel T, Gonzaga Natália A, Simplicio Janaina A, Tirapelli Carlos R
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.
Laboratório de Farmacologia, DEPCH, Escola de Enfermagem de Ribeirão Preto, USP, Ribeirão Preto, São Paulo, Brazil.
Eur J Pharmacol. 2017 Mar 15;799:33-40. doi: 10.1016/j.ejphar.2017.01.036. Epub 2017 Jan 26.
We studied whether the β-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 (O) 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 (HO) 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, p47 or 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.
我们研究了β-肾上腺素能拮抗剂奈必洛尔是否能预防乙醇诱导的大鼠肾皮质活性氧生成和脂质过氧化。雄性Wistar大鼠用乙醇（20% v/v）处理2周。奈必洛尔（10mg/kg/天；口服灌胃）可预防乙醇诱导的肾皮质超氧阴离子（O）生成增加和硫代巴比妥酸反应性物质（TBARS）浓度升高。乙醇降低了肾皮质中硝酸盐/亚硝酸盐（NOx）浓度，而奈必洛尔可预防这种反应。奈必洛尔不影响乙醇诱导的过氧化氢（HO）浓度降低。奈必洛尔可预防乙醇诱导的过氧化氢酶（CAT）活性增加。超氧化物歧化酶（SOD）活性和还原型谷胱甘肽（GSH）水平均不受奈必洛尔或乙醇处理的影响。乙醇和奈必洛尔均不影响肾皮质中Nox1、Nox4、内皮型一氧化氮合酶（eNOS）、神经元型一氧化氮合酶（nNOS）、CAT、Nox组织因子1（Noxo1）、c-Src、p47或超氧化物歧化酶（SOD）同工型的表达。另一方面，乙醇处理可增加Nox2表达，而奈必洛尔可预防这种反应。最后，奈必洛尔降低了蛋白激酶（PK）Cδ和Rac1的表达。我们研究的主要发现是，奈必洛尔通过一种涉及降低NADPH氧化酶催化亚基Nox2表达的机制，预防了乙醇诱导的肾脏活性氧生成和脂质过氧化。此外，我们证明奈必洛尔通过降低PKCδ和Rac1的表达来减少NADPH氧化酶衍生的活性氧，PKCδ和Rac1是NADPH氧化酶的重要激活剂。
