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[目的]研究Nrf2通路损伤与铀诱导的大鼠急性肾毒性的相关性及其机制。[方法]成年雄性SD大鼠随机分成4组,每组6只,采用三种剂量的乙酸双氧铀(即2.5、5、10 mg/kg)单次腹腔注射大鼠,对照组注射生理盐水,收集24 h尿液。2天后,解剖肾脏,检测与分析反映肾功能的生化参数及氧化应激指标;HE染色观察肾组织病理形态变化;采用Western blot检测肾组织细胞中核因子E2相关因子2(Nrf2)、血红素加氧酶-1(HO-1)、谷氨酸-半胱氨酸连接酶催化亚基(GCLC)等基因的蛋白表达。[结果]急性铀中毒引起大鼠尿液中尿素氮与肌酐含量下降,而血清尿素氮和肌酐含量升高,损伤肾组织结构;铀染毒导致肾组织中丙二醛含量上升、还原性谷胱甘肽水平降低,抑制超氧化物歧化酶和过氧化氢酶的活性;低剂量铀染毒使胞核Nrf2含量升高,胞质Nrf2含量减少,增加Nrf2蛋白的核移位。而中、高剂量铀染毒降低Nrf2蛋白表达与核移位,也下调Nrf2通路下游的靶基因HO-1和GCLC的蛋白表达。[结论]急性铀染毒诱导了大鼠肾组织的氧化应激损伤,导致急性肾毒性,Nrf2通路损伤可能介导了铀诱导的大鼠急性肾毒性。
[Objective] To investigate the correlation between Nrf2 pathway damage and uranium-induced acute nephrotoxicity in rats and its mechanism. [Methods] Adult male Sprague-Dawley rats were randomly divided into 4 groups with 6 mice in each group. Rats were injected intraperitoneally with three doses of uranyl acetate (2.5, 2.5 and 10 mg / kg) , Collect 24 h urine. Two days later, the kidneys were dissected and the biochemical parameters and oxidative stress indexes reflecting renal function were detected and analyzed. The pathological changes of renal tissues were observed by HE staining. The expressions of nuclear factor E2 (Nrf2), heme plus Oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC) and other genes. [Results] Acute uranium poisoning caused the decrease of urinary nitrogen and creatinine in the urine of rats and the increase of serum urea nitrogen and creatinine, which damaged the structure of renal tissue. Uranium exposure led to the increase of malondialdehyde content in renal tissue, The activity of SOD and catalase was inhibited by low dose of uranium. The content of Nrf2 in the nucleus increased and the content of Nrf2 in the cytoplasm decreased, which increased the nuclear translocation of Nrf2 protein. However, high and medium dose uranium treatment reduced Nrf2 protein expression and nuclear translocation as well as down-regulated protein expression of target genes HO-1 and GCLC downstream of Nrf2 pathway. [Conclusion] Acute uranium exposure induced oxidative stress injury in rat renal tissue, resulting in acute nephrotoxicity. Injury of Nrf2 pathway may mediate uranium-induced acute nephrotoxicity in rats.