Sp1-mediated upregulation of Prdx6 expression prevents podocyte injury in diabetic nephropathy via mitigation of oxidative stress and ferroptosis.

Abstract

Glomerular podocyte damage is considered to be one of the main mechanisms leading to Diabetic nephropathy (DN). However, the relevant mechanism of podocyte injury is not yet clear. This study aimed to investigate the effect of peroxiredoxin 6 (Prdx6) on the pathogenesis of podocyte injury induced by high glucose (HG). The mouse glomerular podocyte MPC5 was stimulated with 30 nM glucose, and the Prdx6 overexpression vector or specificity protein 1 (Sp1) overexpression vector was transfected into MPC5 cells before the high glucose stimulation. As results, HG treatment significantly reduced the expression of Prdx6 and Sp1 in MPC5 cells. Prdx6 overexpression increased cell viability, while inhibited podocyte death, inflammation and podocyte destruction in HG-induced MPC5 cells. Prdx6 overexpression inhibited HG-induced ROS and MDA production, while restored SOD and GSH activity in MPC5 cells. Prdx6 overexpression also eliminated ferroptosis caused by HG, which was reflected in the suppression of iron accumulation and the increase in SLC7A11 and GPX4 expression. The improvement effect of Prdx6 on HG-induced podocyte damage could be eliminated by erastin. Moreover, Sp1 could bind to the three Sp1 response elements in the Prdx6 promoter, thereby directly regulating the transcriptional activation of Prdx6 in podocytes. Silencing Sp1 could eliminate the effect of Prdx6 on HG-induced podocyte damage. Further, Prdx6 overexpression attenuated renal injuries in streptozotocin-induced DN mice. Sp1-mediated upregulation of Prdx6 expression prevents podocyte injury in diabetic nephropathy via mitigation of oxidative stress and ferroptosis, which may provide new insights for the study of the mechanism of DN.

• Authors: Qianjin Zhang, Yichuan Hu, Jin-E Hu, Ying Ding, Yanqiu Shen, Hong Xu, Huiqin Chen, Ning Wu
• Journal: Life sciences (Life Sci) Vol. 278 Pg. 119529 (Aug 01 2021) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 33894270 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• Piperazines
• Reactive Oxygen Species
• Sp1 Transcription Factor
• erastin
• Peroxiredoxin VI
• Prdx6 protein, mouse
• Glucose

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line
• Cell Survival
• Diabetic Nephropathies (metabolism)
• Epithelial Cells (metabolism)
• Ferroptosis
• Gene Expression Regulation
• Glucose (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Oxidative Stress
• Peroxiredoxin VI (metabolism)
• Piperazines (metabolism)
• Podocytes (metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Sp1 Transcription Factor (metabolism)
• Transcriptional Activation