Division of Nephrology and Hypertension, University of California, Irvine, California, USA.
Am J Physiol Renal Physiol. 2010 Mar;298(3):F662-71. doi: 10.1152/ajprenal.00421.2009. Epub 2009 Dec 9.
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-kappaB 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 downregulation of the antioxidant enzymes.
氧化应激和炎症是慢性肾脏病（CKD）进展的持续特征和主要介质。核因子红细胞 2 相关因子 2（Nrf2）通过协调抗氧化和解毒反应来对抗氧化和亲电应激，从而提供对组织损伤的保护。虽然已经广泛研究了剩余肾脏中氧化应激和炎症的来源，但 CKD 对 Nrf2 激活及其下游基因产物表达的影响尚不清楚，并对此进行了研究。雄性 Sprague-Dawley 大鼠的亚组接受 5/6 肾切除术或假手术，并观察 6 或 12 周。然后收获肾脏，并评估 Nrf2 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。在证实早期研究的基础上，慢性肾衰竭大鼠表现出脂质过氧化增加、谷胱甘肽耗竭、NF-κB 激活、单核细胞浸润以及单核细胞趋化蛋白-1、NAD（P）H 氧化酶、环加氧酶-2 和 12-脂氧合酶在剩余肾脏中的上调，表明存在氧化应激和炎症。尽管存在严重的氧化应激和炎症，但剩余肾脏组织中的 Nrf2 活性（核易位）在 6 周时轻度降低，在 12 周时明显降低，而 Nrf2 抑制剂 Keap1 上调，Nrf2 靶基因的产物[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 周时明显减少。因此，剩余肾脏中的氧化应激和炎症加剧了 Nrf2 激活的明显受损和抗氧化酶的随后下调。
