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Biochim Biophys Acta Mol Cell Res. 2019 Aug;1866(8):1272-1281. doi: 10.1016/j.bbamcr.2019.04.006. Epub 2019 Apr 6.

P53/NRF2 mediates SIRT1's protective effect on diabetic nephropathy.

Author information

1
Department of Nephrology, The First Hospital of Jilin University, 71 Xinmin St., Changchun, Jilin 130021, China.
2
Department of Cardiology, The Second Hospital of Jilin University, 218 Ziqiang St., Changchun, Jilin 130041, China.
3
Department of Hand and Foot Surgery, The First Hospital of Jilin University, 71 Xinmin St., Changchun 130021, China.
4
School of Science and Technology, Georgia Gwinnett College, 1000 University Center Ln., Lawrenceville, GA 30043, USA.
5
Diabetes Metabolism Research Institute, Beckman Research Institute of City of Hope, 1500 E Duarte Rd., Duarte, CA 91010, USA.
6
Department of Nephrology, The First Hospital of Jilin University, 71 Xinmin St., Changchun, Jilin 130021, China. Electronic address: sunwx@jlu.edu.cn.
7
Department of Toxicology and Nutrition, School of Public Health, Shandong University, 44 Wenhua Xi Rd., Jinan, Shandong 250012, China. Electronic address: hwu@sdu.edu.cn.

Abstract

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-α (PFT-α). In the WT mice, SRT2104 enhanced renal SIRT1 expression and activity, deacetylated P53, and activated NRF2 antioxidant signaling, providing remarkable 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-α 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.

KEYWORDS:

Diabetic nephropathy; NRF2; Oxidative stress; P53; SIRT1

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