Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling.
Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling.
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Sirt6 缺陷通过靶向 Notch 信号传导加剧足细胞损伤和蛋白尿。
DOI：
10.1038/s41467-017-00498-4
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发表时间：
2017-09-04
影响因子：
16.6
通讯作者：
Yi F
中科院分区：
文献类型：
--
作者：
Liu M;Liang K;Zhen J;Zhou M;Wang X;Wang Z;Wei X;Zhang Y;Sun Y;Zhou Z;Su H;Zhang C;Li N;Gao C;Peng J;Yi F
足细胞损伤是蛋白尿性肾病的主要决定因素，识别预防足细胞损伤的潜在治疗靶点具有临床重要性。在这里，我们表明，组蛋白去乙酰化酶Sirt6通过Notch信号的表观遗传调节来保护足细胞免受损伤。Sirt6在足细胞病变患者的肾活检中下调，其表达与肾小球滤过率相关。足细胞特异性Sirt6缺失在两个独立的小鼠模型糖尿病肾病和阿霉素诱导的肾病中加重足细胞损伤和蛋白尿。Sirt6在足细胞中具有多效性保护作用，包括抗炎和抗凋亡作用，参与肌动蛋白细胞骨架维持并促进自噬。Sirt6还降低尿激酶纤溶酶原激活物受体的表达，这是足细胞足突消失和蛋白尿的关键因素。在机制上，Sirt6通过使组蛋白H3K9去乙酰化来抑制Notch1和Notch4的转录。我们建议Sirt6作为蛋白尿肾病治疗的潜在治疗靶点。
Podocyte injury is a major determinant of proteinuric kidney disease and the identification of potential therapeutic targets for preventing podocyte injury has clinical importance. Here, we show that histone deacetylase Sirt6 protects against podocyte injury through epigenetic regulation of Notch signaling. Sirt6 is downregulated in renal biopsies from patients with podocytopathies and its expression correlates with glomerular filtration rate. Podocyte-specific deletion of Sirt6 exacerbates podocyte injury and proteinuria in two independent mouse models, diabetic nephropathy, and adriamycin-induced nephropathy. Sirt6 has pleiotropic protective actions in podocytes, including anti-inflammatory and anti-apoptotic effects, is involved in actin cytoskeleton maintenance and promotes autophagy. Sirt6 also reduces urokinase plasminogen activator receptor expression, which is a key factor for podocyte foot process effacement and proteinuria. Mechanistically, Sirt6 inhibits Notch1 and Notch4 transcription by deacetylating histone H3K9. We propose Sirt6 as a potential therapeutic target for the treatment of proteinuric kidney disease.
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RUNX2转录因子负调节SIRT6表达以改变乳腺癌细胞中的葡萄糖代谢。
影响因子：
4
作者：
Choe M;Brusgard JL;Chumsri S;Bhandary L;Zhao XF;Lu S;Goloubeva OG;Polster BM;Fiskum GM;Girnun GD;Kim MS;Passaniti A
通讯作者：
Passaniti A
影响因子：
3.9
作者：
Hwang, Jae-woong;Chung, Sangwoon;Sundar, Isaac K.;Yao, Hongwei;Arunachalam, Gnanapragasam;McBurney, Michael W.;Rahman, Irfan
通讯作者：
Rahman, Irfan
DOI：
10.1042/cs20120190
发表时间：
2013-02
期刊：
Clinical science (London, England : 1979)
影响因子：
--
作者：
Kitada M;Kume S;Takeda-Watanabe A;Kanasaki K;Koya D
通讯作者：
Koya D
影响因子：
64.8
作者：
Guarani V;Deflorian G;Franco CA;Krüger M;Phng LK;Bentley K;Toussaint L;Dequiedt F;Mostoslavsky R;Schmidt MHH;Zimmermann B;Brandes RP;Mione M;Westphal CH;Braun T;Zeiher AM;Gerhardt H;Dimmeler S;Potente M
通讯作者：
Potente M
影响因子：
15.9
作者：
Mallipattu, Sandeep K.;Horne, Sylvia J.;He, John C.
通讯作者：
He, John C.