The crosstalk between Sirt1 and Keap1/Nrf2/ARE anti-oxidative pathway forms a positive feedback loop to inhibit FN and TGF-β1 expressions in rat glomerular mesangial cells
The crosstalk between Sirt1 and Keap1/Nrf2/ARE anti-oxidative pathway forms a positive feedback loop to inhibit FN and TGF-β1 expressions in rat glomerular mesangial cells
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Sirt1 和 Keap1/Nrf2/ARE 抗氧化通路之间的串扰形成正反馈环路，抑制大鼠肾小球系膜细胞中 FN 和 TGF-β1 的表达
DOI：
10.1016/j.yexcr.2017.09.042
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发表时间：
2017-12-01
影响因子：
3.7
通讯作者：
Wei, Wentao
中科院分区：
文献类型：
--
作者：
Huang, Kaipeng;Gao, Xiang;Wei, Wentao
晚期糖基化终产物（AGEs）引起的氧化应激是糖尿病肾病病理进展的罪魁祸首。Sirt 1和Keap 1/Nrf 2/ARE抗氧化通路对糖尿病肾病的发展具有重要的抑制作用。我们的前期研究证实Sirt 1的激活可以通过促进Keap 1/Nrf 2/ARE通路抑制AGEs刺激的肾小球系膜细胞（GMCs）中纤维连接蛋白（FN）和转化生长因子-β 1（TGF-β 1）的上调。然而，其内在机制需要进一步研究。在此，我们发现，伴随着Nrf 2的去乙酰化和泛素化水平的降低，Sirt 1显著增强了Keap 1/Nrf 2/ARE途径的活性，包括降低Keap 1的表达，提高Nrf 2的核含量、ARE结合能力和转录活性，增加Nrf 2的靶基因血红素加氧酶1的蛋白水平，其最终淬灭ROS的过度产生并减轻AGEs处理的GMC中FN和TGF-β 1的积累。Nrf 2的缺失阻断了Sirt 1的肾保护作用。有趣的是，Nrf 2还在蛋白质表达和脱乙酰酶活性水平上正调节Sirt 1，如通过叔丁基氢醌和靶向Nrf 2的特异性siFtNA下调FN和TGF-β 1所证明的。结论：Sirt 1与Keap 1/Nrf 2/ARE抗氧化通路之间的相互作用形成正反馈环，抑制AGEs处理的GMCs中FN和TGF-β 1的蛋白表达。
Oxidative stress aroused by advanced glycation-end products (AGEs) is a culprit in the pathological progression of diabetic nephropathy. Both Sirt1 and the Keap1/Nrf2/ARE anti-oxidative pathway exert crucial inhibitory effects on the development of diabetic nephropathy. Our previous study has confirmed that Sirt1 activation can inhibit the upregulation of fibronectin (FN) and transforming growth factor-beta 1 (TGF-beta 1) by promoting Keap1/Nrf2/ARE pathway in glomerular mesangial cells (GMCs) challenged with AGEs. However, the underlying mechanism needs further investigation. Here, we found that concomitant with deacetylating and reducing the ubiquitination levels of Nrf2, Sirt1 significantly enhanced the activity of Keap1/Nrf2/ARE pathway including decreasing Keap1 expression, promoting the nuclear content, ARE-binding ability, and transcriptional activity of Nrf2, augmenting the protein levels of heme oxygenase 1, a target gene of Nrf2, which eventually quenched ROS overproduction and alleviating FN and TGF-beta 1 accumulation in AGEs-treated GMCs. And depletion of Nrf2 blocked those renoprotective effects of Sirt1. Interestingly, Nrf2 also positively regulated Sirt1 at the protein expression and deacetylase activity levels as evidenced by tert-Butylhydroquinone and specific siFtNA targeting Nrf2 to downregulate FN and TGF-beta 1. In conclusion, the current study basically demonstrated that the crosstalk between Sirt1 and Keap1/Nrf2/ARE anti-oxidative pathway forms a positive feedback loop to inhibit the protein expressions of FN and TGF-beta 1 in AGEs-treated GMCs.