P53/NRF2 mediates SIRT1's protective effect on diabetic nephropathy
P53/NRF2 mediates SIRT1's protective effect on diabetic nephropathy
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P53/NRF2介导SIRT1对糖尿病肾病的保护作用
DOI：
10.1016/j.bbamcr.2019.04.006
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发表时间：
2019-08-01
影响因子：
5.1
通讯作者：
Wu, Hao
中科院分区：
文献类型：
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作者：
Ma, Fuzhe;Wu, Junduo;Wu, Hao
糖尿病肾病（diabetic nephropathy，DN）是终末期肾病的主要病因，严重威胁着人类的健康。先前的研究报道了sirtuin 1（SIRT 1）在DN中的保护作用，鼓励研究更有效和特异性的SIRT 1激活剂。SRT 2104是一种新型的、高选择性的SIRT 1小分子激活剂，其对DN的作用和机制尚不清楚。为此，用SRT 2104处理链脲霉素诱导的C57 BL/6野生型（WT）糖尿病小鼠24周。为了确定SRT 2104是否通过抑制SIRT 1的P53 - a底物起作用，在SRT 2104存在下向WT糖尿病小鼠施用P53激活剂nutlin 3a。为了测试核因子红细胞2相关因子2（NRF 2）-细胞抗氧化剂的主人-是否介导SIRT 1和P53的作用，WT和NRF 2基因敲除（KO）糖尿病小鼠用SRT 2104或P53抑制剂匹非亭-α（PFT-α）处理。在WT小鼠中，SRT 2104增强肾脏SIRT 1表达和活性，脱乙酰化P53，并激活NRF 2抗氧化剂信号传导，对DM诱导的肾脏氧化应激、炎症、纤维化、肾小球重塑和白蛋白尿提供有力保护。在nutlin 3a的存在下，这些作用被完全消除。Nrf 2基因的缺失完全消除了SRT 2104和PFT-α在提高抗氧化剂和改善DN方面的功效，尽管它们在Nrf 2 KO小鼠中具有激活SIRT 1和抑制P53的能力。本研究报告了SRT 2104对DN的有益作用，揭示了调节DN发病机制的SIRT 1/P53/NRF 2通路。
Diabetic nephropathy (DN) is the leading cause of end stage renal disease, posing a severe threat to public health. Previous studies reported the protective role of sirtuin 1 (SIRT1) in DN, encouraging the investigation of more potent and specific SIRT1 activators. SRT2104 is a novel, first-in-class, highly selective small-molecule activator of SIRT1, with its effect and mechanism unknown on DN. To this end, streptozotocin-induced C57BL/6 wild-type (WT) diabetic mice were treated with SRT2104, for 24 weeks. To determine whether SRT2104 acted through inhibition of P53 - a substrate of SIRT1, the P53 activator nutlin3a was administered to the WT diabetic mice in the presence of SRT2104. In order to test whether nuclear factor erythroid 2-related factor 2 (NRF2) - the master of cellular antioxidants - mediated SIRT1 and P53's actions, WT and Nrf2 gene knockout (KO) diabetic mice were treated with SRT2104 or the P53 inhibitor pifithrin-alpha (PFT-alpha). In the WT mice, SRT2104 enhanced renal SIRT1 expression and activity, deacetylated P53, and activated NRF2 antioxidant signaling, providing remarkble protection against the DM-induced renal oxidative stress, inflammation, fibrosis, glomerular remodeling and albuminuria. These effects were completely abolished in the presence of nutlin3a. Deletion of the Nrf2 gene completely abrogated the efficacies of SRT2104 and PFT-alpha in elevating antioxidants and ameliorating DN, despite their abilities to activate SIRT1 and inhibit P53 in the Nrf2 KO mice. The present study reports the beneficial effects of SRT2104 on DN, uncovering a SIRT1/P53/NRF2 pathway that modulates the pathogenesis of DN.