Sodium butyrate activates NRF2 to ameliorate diabetic nephropathy possibly via inhibition of HDAC
Sodium butyrate activates NRF2 to ameliorate diabetic nephropathy possibly via inhibition of HDAC
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丁酸钠可能通过抑制 HDAC 激活 NRF2 以改善糖尿病肾病
DOI：
10.1530/joe-16-0322
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发表时间：
2017-01-01
影响因子：
4
通讯作者：
Wu, Hao
中科院分区：
文献类型：
--
作者：
Dong, Wenpeng;Jia, Ye;Wu, Hao
氧化应激参与糖尿病肾病（DN）的发病机制。核因子红细胞2相关因子2 （NRF2）在细胞防御氧化应激中起关键作用。NRF2激活剂对DN有良好的预防作用。丁酸钠（NaB）是一种已知的NRF2激活剂。然而，目前尚不清楚NRF2是否需要NaB对DN的保护。因此，链状zotocin诱导的糖尿病C57BL/6 Nrf2基因敲除小鼠及其野生型小鼠在存在或不存在NaB的情况下治疗20周。糖尿病小鼠出现了明显的肾脏氧化损伤、炎症、细胞凋亡、纤维化、病理改变和蛋白尿。NaB抑制组蛋白去乙酰化酶（HDAC）活性，提高Nrf2及其下游靶点血红素加氧酶1和NAD(P)H脱氢酶醌1的表达。值得注意的是，Nrf2基因的缺失完全消除了NaB对Nrf2信号的激活和对糖尿病诱导的肾损伤的保护。有趣的是，在糖尿病和非糖尿病条件下，kelch样ech相关蛋白1 （NRF2的负调节因子）的表达并未被NaB改变。此外，NaB不促进NRF2核易位。因此，本研究首次表明NRF2在NaB对DN的保护中起关键作用。其他研究结果表明，NaB可能在转录水平上激活Nrf2，可能是通过抑制HDAC活性。
Oxidative stress contributes to the pathogenesis of diabetic nephropathy (DN). Nuclear factor erythroid 2-related factor 2 (NRF2) plays a key role in cellular defense against oxidative stress. NRF2 activators have shown promising preventive effects on DN. Sodium butyrate (NaB) is a known activator of NRF2. However, it is unknown whether NRF2 is required for NaB protection against DN. Therefore, streptozotocin-induced diabetic C57BL/6 Nrf2 knockout and their wild-type mice were treated in the presence or absence of NaB for 20 weeks. Diabetic mice, but not NaB-treated diabetic mice, developed significant renal oxidative damage, inflammation, apoptosis, fibrosis, pathological changes and albuminuria. NaB inhibited histone deacetylase (HDAC) activity and elevated the expression of Nrf2 and its downstream targets heme oxygenase 1 and NAD(P)H dehydrogenase quinone 1. Notably, deletion of the Nrf2 gene completely abolished NaB activation of NRF2 signaling and protection against diabetes-induced renal injury. Interestingly, the expression of Kelch-like ECH-associated protein 1, the negative regulator of NRF2, was not altered by NaB under both diabetic and non diabetic conditions. Moreover, NRF2 nuclear translocation was not promoted by NaB. Therefore, the present study indicates, for the first time, that NRF2 plays a key role in NaB protection against DN. Other findings suggest that NaB may activate Nrf2 at the transcriptional level, possibly by the inhibition of HDAC activity.