Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure
Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure
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DOI：
10.1152/ajprenal.00421.2009
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发表时间：
2010-03-01
影响因子：
4.2
通讯作者：
Vaziri, Nosratola D.
中科院分区：
文献类型：
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作者：
Kim, Hyun Ju;Vaziri, Nosratola D.
Kim HJ，Vaziri ND.慢性肾功能衰竭中受损的Nrf 2-Keap 1通路对氧化应激和炎症的作用美国肾脏生理学杂志298：F662-F671，2010年。首次发表于2009年12月9日; doi：10.1152/ajprenal.00421.2009。氧化应激和炎症是慢性肾脏病（CKD）进展的恒定特征和主要介质。核因子红细胞-2相关因子-2（Nrf 2）通过协调对氧化和亲电子应激的抗氧化和解毒反应来保护组织免受损伤。虽然残留肾脏中氧化应激和炎症的来源已被广泛表征，但CKD对Nrf 2激活及其下游基因产物表达的影响尚不清楚，并进行了研究。雄性Sprague-Dawley大鼠分为5/6肾切除组和假手术组，观察6周和12周。然后收获肾脏，并评估Nrf 2活性及其下游靶基因产物（抗氧化剂和II相酶）。此外，还研究了促进炎症和氧化应激的关键因素。证实了早期研究，慢性肾衰竭大鼠表现出脂质过氧化、谷胱甘肽耗竭、NF-κ B活化、单核细胞浸润增加，以及残余肾脏中单核细胞趋化蛋白-1、NAD（P）H氧化酶、环氧合酶-2和12-脂氧合酶上调，表明氧化应激和炎症。尽管有严重的氧化应激和炎症，残余肾组织Nrf 2活性（核转位）在6周时轻度减少，在12周时显著减少，而Nrf 2阻遏物Keap 1上调，Nrf 2靶基因产物[过氧化氢酶，超氧化物歧化酶，谷胱甘肽过氧化物酶，血红素加氧酶-1，NAD（P）H醌氧化还原酶，和谷氨酸-半胱氨酸连接酶]在6周时减少或不变，在12周时显著减少。因此，残余肾脏中的氧化应激和炎症通过Nrf 2活化的明显损害和随后的抗氧化酶的下调而复合。
Kim HJ, Vaziri ND. Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure. Am J Physiol Renal Physiol 298: F662-F671, 2010. First published December 9, 2009; doi:10.1152/ajprenal.00421.2009.-Oxidative stress and inflammation are constant features and major mediators of progression of chronic kidney disease (CKD). Nuclear factor erythroid-2-related factor-2 (Nrf2) confers protection against tissue injury by orchestrating antioxidant and detoxification responses to oxidative and electrophilic stress. While sources of oxidative stress and inflammation in the remnant kidney have been extensively characterized, the effect of CKD on Nrf2 activation and expression of its downstream gene products is unknown and was investigated. Subgroups of male Sprague-Dawley rats were subjected to 5/6 nephrectomy or sham operation and observed for 6 or 12 wk. Kidneys were then harvested, and Nrf2 activity and its downstream target gene products (antioxidant and phase II enzymes) were assessed. In addition, key factors involved in promoting inflammation and oxidative stress were studied. In confirmation of earlier studies, rats with chronic renal failure exhibited increased lipid peroxidation, glutathione depletion, NF-kappa B activation, mononuclear cell infiltration, and upregulation of monocyte chemoattractant protein-1, NAD(P)H oxidase, cyclooxygenase-2, and 12-lipoxygenase in the remnant kidney pointing to oxidative stress and inflammation. Despite severe oxidative stress and inflammation, remnant kidney tissue Nrf2 activity (nuclear translocation) was mildly reduced at 6 wk and markedly reduced at 12 wk, whereas the Nrf2 repressor Keap1 was upregulated and the products of Nrf2 target genes [catalase, superoxide dismutase, glutathione peroxidase, heme oxygenase-1, NAD(P)H quinone oxidoreductase, and glutamate-cysteine ligase] were reduced or unchanged at 6 wk and significantly diminished at 12 wk. Thus oxidative stress and inflammation in the remnant kidney are compounded by conspicuous impairment of Nrf2 activation and consequent down-regulation of the antioxidant enzymes.