Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling

Min Liu, Kaili Liang, Junhui Zhen, Meng Zhou, Xiaojie Wang, Ziying Wang, Xinbing Wei, Yan Zhang, Yu Sun, Zhuanli Zhou, Hua Su, Chun Zhang, Ningjun Li, Chengjiang Gao, Jun Peng and Fan Yi ()
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Min Liu: Shandong University School of Medicine
Kaili Liang: Shandong University School of Medicine
Junhui Zhen: Shandong University School of Medicine
Meng Zhou: Shandong University School of Medicine
Xiaojie Wang: Shandong University School of Medicine
Ziying Wang: Shandong University School of Medicine
Xinbing Wei: Shandong University School of Medicine
Yan Zhang: Shandong University School of Medicine
Yu Sun: Shandong University School of Medicine
Zhuanli Zhou: Huazhong University of Science and Technology
Hua Su: Huazhong University of Science and Technology
Chun Zhang: Huazhong University of Science and Technology
Ningjun Li: Virginia Commonwealth University
Chengjiang Gao: Shandong University School of Medicine
Jun Peng: Shandong University
Fan Yi: Shandong University School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00498-4

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