Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression
Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression
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DOI：
10.1016/j.kint.2016.08.023
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发表时间：
2017-02-01
影响因子：
19.6
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
--
作者：
Nezu, Masahiro;Souma, Tomokazu;Yamamoto, Masayuki
急性肾损伤是一种严重危害人类健康的疾病，在住院患者中发病率很高，是慢性肾脏病发病的重要原因之一。急性肾损伤的潜在机制涉及缺血-再灌注损伤，缺血-再灌注损伤继而诱导氧化应激并引起器官损伤。Nrf 2是调节细胞对氧化应激反应的主转录因子。在这里，我们使用遗传学和药理学方法研究了Nrf 2在小鼠缺血再灌注损伤诱导的肾损伤进展中的作用。全局和肾小管特异性Nrf 2激活增强抗氧化剂和NADPH合成酶（包括葡萄糖-6-磷酸脱氢酶）的基因表达，并改善外髓质损伤的起始和皮质肾小管损伤的进展。骨髓特异性Nrf 2激活无效。在损伤的初始阶段短期施用Nrf 2诱导剂CDDO改善了肾小管损伤的晚期阶段。这种诱导剂有效地保护了人近端肾小管细胞系HK-2免受氧化应激介导的细胞死亡，而葡萄糖-6-磷酸脱氢酶敲除增加了细胞内活性氧。这些发现表明，在损伤的初始阶段，肾小管过度激活Nrf 2通过诱导抗氧化酶和NADPH合成来防止活性氧介导的肾小管损伤的进展。因此，Nrf 2可能是预防急性肾损伤向慢性肾病转变的有希望的治疗靶点。
Acute kidney injury is a devastating disease with high morbidity in hospitalized patients and contributes to the pathogenesis of chronic kidney disease. An underlying mechanism of acute kidney injury involves ischemia-reperfusion injury which, in turn, induces oxidative stress and provokes organ damage. Nrf2 is a master transcription factor that regulates the cellular response to oxidative stress. Here, we examined the role of Nrf2 in the progression of ischemia-reperfusion injury-induced kidney damage in mice using genetic and pharmacological approaches. Both global and tubular-specific Nrf2 activation enhanced gene expression of antioxidant and NADPH synthesis enzymes, including glucose-6-phosphate dehydrogenase, and ameliorated both the initiation of injury in the outer medulla and the progression of tubular damage in the cortex. Myeloid-specific Nrf2 activation was ineffective. Short-term administration of the Nrf2 inducer CDDO during the initial phase of injury ameliorated the late phase of tubular damage. This inducer effectively protected the human proximal tubular cell line HK-2 from oxidative stress-mediated cell death while glucose-6-phosphate dehydrogenase knockdown increased intracellular reactive oxygen species. These findings demonstrate that tubular hyperactivation of Nrf2 in the initial phase of injury prevents the progression of reactive oxygen species-mediated tubular damage by inducing antioxidant enzymes and NADPH synthesis. Thus, Nrf2 may be a promising therapeutic target for preventing acute kidney injury to chronic kidney disease transition.