Nrf2 deficiency promotes the progression from acute tubular damage to chronic renal fibrosis following unilateral ureteral obstruction
Nrf2 deficiency promotes the progression from acute tubular damage to chronic renal fibrosis following unilateral ureteral obstruction
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Nrf2缺乏促进单侧输尿管梗阻后急性肾小管损伤进展为慢性肾纤维化
DOI：
10.1093/ndt/gfx299
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发表时间：
2018-05-01
影响因子：
6.1
通讯作者：
Zhou, Hua
中科院分区：
文献类型：
--
作者：
Kong, Weiwei;Fu, Jingqi;Zhou, Hua
背景
核因子红细胞2相关因子2（Nrf 2）是细胞对氧化应激反应的中心介质。我们假设Nrf 2调节从急性肾小管损伤到肾纤维化的进展。我们询问Nrf 2缺失是否会增加单侧输尿管梗阻（UUO）小鼠的肾损伤。
方法
我们探讨了UUO后Nrf 2 +/+小鼠肾损伤和Nrf 2表达的时间过程。我们比较了UUO后Nrf 2 +/+和Nrf 2-/-小鼠的肾小管损伤、转分化[波形蛋白、增殖细胞核抗原（PCNA）]、纤维化[纤连蛋白、α-平滑肌肌动蛋白（SMA）]、抗氧化和炎症反应。我们研究了急性、亚急性和慢性肾小管间质性肾炎（TIN）患者肾活检中的Nrf 2。
结果
在Nrf 2 +/+小鼠中，肾Nrf 2表达和Nrf 2调节的谷氨酸-半胱氨酸连接酶催化（Gclc）和血红素加氧酶-1（Ho-1）升高，肾损伤发生在UUO后2 - 14天。在UUO后第2天，与Nrf 2 +/+小鼠相比，Nrf 2-/-小鼠的肾小管损伤、凋亡细胞数、切割的半胱氨酸天冬氨酸蛋白酶3和切割的聚ADP核糖聚合酶增加。在第5天，波形蛋白和PCNA的蛋白水平以及两种蛋白的共表达细胞增加。第14天，纤连蛋白和α-SMA蛋白水平升高。Nrf 2缺失降低抗氧化基因（Gclc和Ho-1）的表达，增加炎症反应基因（Tgfβ、Tnf、IL-6、IL-1β和F4/80）的表达。最后，在TIN患者的肾活检组织中，Nrf 2表达上调。
结论
在UUO后，Nrf 2缺乏增加了肾小管损伤、转分化、纤维化和炎症反应，同时降低了抗氧化反应。Nrf 2在UUO肾小管间质纤维化发展中的肾脏保护作用可能是通过抗氧化和抗炎途径介导的。
Background
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a central mediator of cellular responses to oxidative stress. We hypothesized that Nrf2 modulates progression from acute tubular damage to renal fibrosis. We asked whether Nrf2 deletion increases renal injury in mice following unilateral ureteral obstruction (UUO).
Methods
We explored the time course of renal injury and Nrf2 expression in Nrf2+/+ mice following UUO. We compared Nrf2+/+ and Nrf2-/- mice following UUO in tubular damage, transdifferentiation [vimentin, proliferating cell nuclear antigen (PCNA)], fibrosis [fibronectin, α-smooth muscle actin (SMA)], antioxidative and inflammatory responses. We studied Nrf2 in renal biopsies of patients with acute, subacute and chronic tubulointerstitial nephritis (TIN).
Results
In Nrf2+/+ mice, renal Nrf2 expression and Nrf2-regulated glutamate-cysteine ligase catalytic (Gclc) and heme oxygenase-1 (Ho-1) were elevated, and renal injury occurred between 2 and 14 days after UUO. On Day 2 following UUO, in Nrf2-/- mice compared with Nrf2+/+ mice, tubular damage, apoptotic cell numbers, cleaved caspase3 and cleaved-poly ADP-ribose polymerase were increased. On Day 5, protein levels of vimentin and PCNA and the co-expressed cells of both proteins were increased. On Day 14, fibronectin and α-SMA protein levels were increased. Nrf2 deletion decreased expression of antioxidative genes (Gclc and Ho-1) and increased expression of inflammatory response genes (Tgfβ, Tnf, IL-6, IL-1β and F4/80). Finally, Nrf2 expression was upregulated in renal biopsies of patients with TIN.
Conclusions
Following UUO, Nrf2 deficiency increased tubular damage, transdifferentiation, fibrosis and inflammatory response while decreasing antioxidative responses. The renal protective role of Nrf2 in the development of tubulointerstitial fibrosis in UUO may be mediated by antioxidative and anti-inflammatory pathways.