Role of impaired Nrf2 activation in the pathogenesis of oxidative stress and inflammation in chronic tubulo-interstitial nephropathy
Role of impaired Nrf2 activation in the pathogenesis of oxidative stress and inflammation in chronic tubulo-interstitial nephropathy
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DOI：
10.1093/ndt/gft022
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发表时间：
2013-08-01
影响因子：
6.1
通讯作者：
Vaziri, Nosratola D.
中科院分区：
文献类型：
--
作者：
Aminzadeh, Mohammad A.;Nicholas, Susanne B.;Vaziri, Nosratola D.
背景肾小管间质性肾病（TIN）是慢性肾脏病（CKD）的常见原因。摄入含腺嘌呤的饮食导致2，8-二羟基腺嘌呤在肾小管中蓄积，引发大鼠严重的慢性TIN和进行性CKD。该模型中的CKD与氧化应激和炎症相关，并在很大程度上由氧化应激和炎症驱动。自发性局灶节段性肾小球硬化大鼠和5/6肾切除术诱导的CKD大鼠的氧化应激和炎症与核因子-红细胞2相关因子2（Nrf 2）的活化受损相关，Nrf 2是编码许多抗氧化和解毒酶的基因的主要调节因子。TIN对Nrf 2通路及其关键靶基因的影响尚不清楚，本文对其进行了研究。将SD大鼠随机分为对照组和腺嘌呤治疗组（含0.7%腺嘌呤的大鼠饲料2周），并随访4周。腺嘌呤处理的动物表现出明显的氮质血症，尿浓缩能力受损，严重的肾小管和肾小球损伤，间质炎症和纤维化。这与NAD（P）H氧化酶、环氧合酶-2和12-脂氧合酶的表达增加以及促炎细胞因子和趋化因子的主要调节因子NF-κ B的活化有关。腺嘌呤处理动物肾脏中的氧化应激和炎症伴随着Nrf 2活化受损及其靶基因产物（包括过氧化氢酶、血红素加氧酶-1和谷氨酸-半胱氨酸连接酶）的下调。慢性TIN与受损的Nrf 2活性相关，这有助于氧化应激和炎症的发病机制，并放大其对肾脏的损害作用。
Background. Tubulo-interstitial nephropathy (TIN) is a common cause of chronic kidney disease (CKD). Consumption of an adenine-containing diet causes the accumulation of 2,8-dihydroxyadenine in the renal tubules triggering intense chronic TIN and progressive CKD in rats. CKD in this model is associated with, and largely driven by, oxidative stress and inflammation. Oxidative stress and inflammation in rats with spontaneous focal segmental glomerulosclerosis and rats with CKD induced by 5/6 nephrectomy are associated with an impaired activation of nuclear factor-erythroid-2-related factor 2 (Nrf2) which is the master regulator of genes encoding many antioxidant and detoxifying enzymes. The effect of TIN on the Nrf2 pathway and its key target genes is unknown and was investigated here.Methods. Sprague-Dawley rats were randomized to control and adenine-treated (rat chow-containing 0.7% adenine for 2 weeks) groups and followed up for 4 weeks.Results. The adenine-treated animals exhibited marked azotemia, impaired urinary concentrating capacity, intense tubular and glomerular damage, interstitial inflammation and fibrosis. This was associated with an increased expression of NAD(P) H oxidase, cyclooxygenase-2 and 12-lipoxygenase, and activation of NF-kappa B, the master regulator of pro-inflammatory cytokines and chemokines. Oxidative stress and inflammation in the kidneys of adenine-treated animals was accompanied by an impaired activation of Nrf2 and down-regulation of its target gene products including, catalase, heme oxygenase-1 and glutamate-cysteine ligase.Conclusions. Chronic TIN is associated with impaired Nrf2 activity which contributes to the pathogenesis of oxidative stress and inflammation and amplifies their damaging effects on the kidney.