Liu Min, Liang Kaili, Zhen Junhui, Zhou Meng, Wang Xiaojie, Wang Ziying, Wei Xinbing, Zhang Yan, Sun Yu, Zhou Zhuanli, Su Hua, Zhang Chun, Li Ningjun, Gao Chengjiang, Peng Jun, Yi Fan
Department of Pharmacology, Shandong University School of Medicine, Jinan, 250012, China.
Department of Pathology, Shandong University School of Medicine, Jinan, 250012, China.
Nat Commun. 2017 Sep 4;8(1):413. doi: 10.1038/s41467-017-00498-4.
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.Podocytes are essential components of the renal glomerular filtration barrier and podocyte dysfunction leads to proteinuric kidney disease. Here Liu et al. show that Sirt6 protects podocytes from apoptosis and inflammation by increasing autophagic flux through inhibition of the Notch pathway.
足细胞损伤是蛋白尿性肾病的主要决定因素，确定预防足细胞损伤的潜在治疗靶点具有临床重要性。在此，我们表明组蛋白脱乙酰酶Sirt6通过Notch信号通路的表观遗传调控来保护足细胞免受损伤。在足细胞病患者的肾活检组织中，Sirt6表达下调，其表达与肾小球滤过率相关。在两种独立的小鼠模型（糖尿病肾病和阿霉素诱导的肾病）中，足细胞特异性缺失Sirt6会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的维持并促进自噬。Sirt6还降低尿激酶型纤溶酶原激活物受体的表达，该受体是足细胞足突消失和蛋白尿的关键因素。从机制上讲，Sirt6通过使组蛋白H3K9去乙酰化来抑制Notch1和Notch4转录。我们提出Sirt6作为治疗蛋白尿性肾病的潜在治疗靶点。足细胞是肾小球滤过屏障的重要组成部分，足细胞功能障碍会导致蛋白尿性肾病。在此，刘等人表明，Sirt6通过抑制Notch途径增加自噬通量，从而保护足细胞免受凋亡和炎症的影响。
