硫化氢（H2S）通过 Nrf2-NF-κB 通路减轻铀诱导的急性肾毒性及其氧化应激和炎症反应。
Hydrogen sulfide (H2S) attenuates uranium-induced acute nephrotoxicity through oxidative stress and inflammatory response via Nrf2-NF-κB pathways.
机构信息
Institute of Biology, Pharmacy and Life College, University of South China, Changsheng West Road 28, Hengyang City, Hunan Province 421001, PR China.
Key Discipline Laboratory for National Defense for Biotechnology in Uranium Mining and Hydrometallurgy, University of South China, Changsheng West Road 28, Hengyang City, Hunan Province 421001, PR China.
出版信息
Chem Biol Interact. 2015 Dec 5;242:353-62. doi: 10.1016/j.cbi.2015.10.021. Epub 2015 Oct 31.
As an endogenous gaseous mediator, H2S exerts anti-oxidative, anti-inflammatory and cytoprotective effects in kidneys. This study was designed to investigate the protective effect of H2S against uranium-induced nephrotoxicity in adult SD male rats after in vivo effect of uranium on endogenous H2S formation was explored in kidneys. The levels of endogenous H2S and H2S-producing enzymes (CBS and CSE) were measured in renal homogenates from rats intoxicated by an intraperitoneally (i.p.) injection of uranyl acetate at a single dose of 2.5, 5 or 10 mg/kg. In rats injected i.p. with uranyl acetate (5 mg/kg) or NaHS (an H2S donor, 28 or 56 μmol/kg) alone or in combination, we determined biochemical parameters and histopathological alteration to assess kidney function, examined oxidative stress markers, and investigated Nrf2 and NF-κB pathways in kidney homogenates. The results suggest that uranium intoxication in rats decreased endogenous H2S generation as well as CBS and CSE protein expression. NaHS administration in uranium-intoxicated rats ameliorated the renal biochemical indices and histopathological effects, lowered MDA accumulation, and restored GSH level and anti-oxidative enzymes activities like SOD, CAT, GPx and GST. NaHS treatment in uranium-intoxicated rats activated uranium-inhibited protein expression and nuclear translocation of transcription factor Nrf2, which increased protein expression of downstream target-Nrf2 genes HO-1, NQO-1, GCLC, and TXNRD-1. NaHS administration in uranium-intoxicated rats inhibited uranium-induced nuclear translocation and phosphorylation of transcription factor κB/p65, which decreased protein expression of target-p65 inflammatory genes TNF-α, iNOS, and COX-2. Taken together, these data implicate that H2S can afford protection to rat kidneys against uranium-induced adverse effects through induction of antioxidant defense by activating Nrf2 pathway and reduction of inflammatory response by suppressing NF-κB pathway.
作为一种内源性气态介质，H2S 在肾脏中发挥抗氧化、抗炎和细胞保护作用。本研究旨在探讨 H2S 对成年雄性 SD 大鼠铀诱导肾毒性的保护作用，方法是在体内研究铀对肾脏内源性 H2S 生成的影响。用铀乙酸盐（2.5、5 或 10mg/kg，腹腔内注射）单次处理大鼠，测量肾匀浆中内源性 H2S 水平和 H2S 产生酶（CBS 和 CSE）的水平。在单独或联合腹腔注射铀乙酸盐（5mg/kg）或 NaHS（H2S 供体，28 或 56μmol/kg）的大鼠中，我们测定了生化参数和组织病理学改变，以评估肾功能，检测氧化应激标志物，并研究肾匀浆中的 Nrf2 和 NF-κB 途径。结果表明，铀中毒使大鼠内源性 H2S 生成以及 CBS 和 CSE 蛋白表达减少。在铀中毒大鼠中给予 NaHS 可改善肾脏生化指标和组织病理学效应，降低 MDA 积累，恢复 GSH 水平和抗氧化酶活性，如 SOD、CAT、GPx 和 GST。NaHS 处理可激活铀抑制的转录因子 Nrf2 的蛋白表达和核转位，增加下游靶基因 Nrf2 基因 HO-1、NQO-1、GCLC 和 TXNRD-1 的蛋白表达。NaHS 处理可抑制铀诱导的转录因子 NF-κB/p65 的核转位和磷酸化，降低靶基因 p65 炎症基因 TNF-α、iNOS 和 COX-2 的蛋白表达。总之，这些数据表明，H2S 通过激活 Nrf2 途径诱导抗氧化防御和抑制 NF-κB 途径减少炎症反应，为大鼠肾脏提供对抗铀诱导的不良反应的保护。
Zotero 插件