PARP-1 and SIRT-1 are Interacted in Diabetic Nephropathy by Activating AMPK/PGC-1α Signaling Pathway

Hengmei Zhu; Zhi Fang; Jiehui Chen; Yun Yang; Jiacheng Gan; Liang Luo; Xiaojiang Zhan

doi:10.2147/DMSO.S291314

PARP-1 and SIRT-1 are Interacted in Diabetic Nephropathy by Activating AMPK/PGC-1α Signaling Pathway

Diabetes Metab Syndr Obes. 2021 Jan 25:14:355-366. doi: 10.2147/DMSO.S291314. eCollection 2021.

Authors

Hengmei Zhu^#^{1

2}, Zhi Fang^#³, Jiehui Chen², Yun Yang², Jiacheng Gan⁴, Liang Luo⁵, Xiaojiang Zhan¹

Affiliations

¹ Department of Nephrology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China.
² Department of Nephrology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518000, People's Republic of China.
³ Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China.
⁴ Department of Nuclear Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen 518000, People's Republic of China.
⁵ Department of Cardiology, Ganzhou People's Hospital, Ganzhou 341000, People's Republic of China.

^# Contributed equally.

Abstract

Introduction: Diabetic nephropathy (DN) is a metabolic disorder characterized by the accumulation of extracellular matrix (ECM). This study aims to investigate whether exists an interplay between poly (ADP-ribose) polymerase 1 (PARP-1) and sirtuin 1 (SIRT-1) in DN via AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) signaling pathway.

Methods: Eight-week-old male obese leptin-resistant (db/db) mice and nondiabetic control male C57BLKs/J (db/m) mice were used in this study. Body weight and blood glucose were evaluated after 6 h of fasting, which continues for 4 weeks. The kidney tissues were dissected for Western blot, immunofluorescence (IF) assay. Besides, PARP activity assay, MTT assay, NAD⁺ qualification, Western blot and IF were also performed to detect the level and relation of PARP-1 and SIRT-1 in mouse mesangial cells (MCs) with or without high glucose followed by inhibiting or elevating PARP-1 and SIRT-1, respectively.

Results: Western blotting shows PARP-1 and ECM marker fibronectin (FN) are upregulated while SIRT-1 is downregulated in db/db mice (p<0.05) or in mouse MCs with high glucose (p<0.05), which are significantly restored by PARP-1 inhibitor (PJ34) (p<0.05) and SIRT-1 lentiviral transfected treatment (p<0.05), or worsened by SIRT-1 inhibitor EX527 (p<0.05). PJ34 treatment (p < 0.05) or SIRT-1 overexpression (p < 0.05) could increase PGC-1α and p-AMPK levels, concomitant with down expression of FN, however, were reversed in the presence of EX527 (p<0.05).

Discussion: Our results suggest an important relationship between PARP-1 and SIRT-1 through AMPK-PGC-1α pathway, indicating a potential therapeutic method for DN.

Keywords: AMPK/PGC-1α signaling pathway; PARP-1; SIRT-1; diabetic nephropathy.

Grants and funding

This work was supported by the Basic Research Project of Shenzhen Science and Technology Innovation Commission (JCYJ20160429181842402, JCYJ20190809112003711) and Jiangxi Natural Sciences Youth Science Foundation-Youth Fund Project (20202BAB216007).