Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus.
Hyperactivation of Nrf2 in early tubular development induces nephrogenic diabetes insipidus.
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肾小管发育早期Nrf2的过度激活可导致肾源性尿崩症。
DOI：
10.1038/ncomms14577
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发表时间：
2017-02-24
影响因子：
16.6
通讯作者：
Yamamoto M
中科院分区：
文献类型：
--
作者：
Suzuki T;Seki S;Hiramoto K;Naganuma E;Kobayashi EH;Yamaoka A;Baird L;Takahashi N;Sato H;Yamamoto M
NF-E2 相关因子 2 (Nrf2) 调节细胞对氧化和亲电应激的反应。 Keap1 缺失会增加 Nrf2 蛋白水平，Keap1 缺失小鼠会因 Nrf2 过度激活而死于食管角化过度。在这里，我们发现，在Keap1缺失的小鼠中，食管Nrf2的缺失可以让它们存活到成年，但这些动物会出现低渗透压的多尿和双侧肾积水。这种表型是由水重吸收缺陷引起的，而水重吸收缺陷是肾脏中水通道蛋白 2 水平降低的结果。肾小管中 Keap1 的缺失会促进肾性尿崩症的特征，证实发育中的肾小管细胞中 Nrf2 的激活会导致水重吸收缺陷。这些发现表明，在发育过程中应严格控制 Nrf2 活性，以维持肾脏稳态。此外，Keap1缺失小鼠中Nrf2的组织特异性消融可能会创建有用的动物模型来揭示Nrf2的新生理功能。 Nrf2 通过调节参与解毒途径的酶的表达来调节氧化和亲电应激反应。这里铃木等人。表明早期肾小管发育中 Nrf2 的激活通过调节水通道蛋白 2 的表达和运输以及水渗透性促进肾性尿崩症。
NF-E2-related factor-2 (Nrf2) regulates cellular responses to oxidative and electrophilic stress. Loss of Keap1 increases Nrf2 protein levels, and Keap1-null mice die of oesophageal hyperkeratosis because of Nrf2 hyperactivation. Here we show that deletion of oesophageal Nrf2 in Keap1-null mice allows survival until adulthood, but the animals develop polyuria with low osmolality and bilateral hydronephrosis. This phenotype is caused by defects in water reabsorption that are the result of reduced aquaporin 2 levels in the kidney. Renal tubular deletion of Keap1 promotes nephrogenic diabetes insipidus features, confirming that Nrf2 activation in developing tubular cells causes a water reabsorption defect. These findings suggest that Nrf2 activity should be tightly controlled during development in order to maintain renal homeostasis. In addition, tissue-specific ablation of Nrf2 in Keap1-null mice might create useful animal models to uncover novel physiological functions of Nrf2. Nrf2 regulates oxidative and electrophilic stress responses by modulating the expression of enzymes involved in detoxification pathways. Here Suzuki et al. show that Nrf2 activation in early tubular development promotes nephrogenic diabetes insipidus by regulating aquaporin 2 expression and trafficking and water permeability.