Li JM, Song ZH, Li Y, Chen HW, Li H, Yuan L, Li J, Lv WY, Liu L, Wang N. NR4A1 silencing alleviates high-glucose-stimulated HK-2 cells pyroptosis and fibrosis via hindering NLRP3 activation and PI3K/AKT pathway. World J Diabetes 2025; 16(3): 97544 [DOI: 10.4239/wjd.v16.i3.97544]
Corresponding Author of This Article
Na Wang, Doctor, Additional Professor, Department of General Medicine, Affiliated Hospital of Jining Medical University, No. 89 Guhuai Road, Jining 272029, Shandong Province, China. wangna19840906@163.com
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Diabetes. Mar 15, 2025; 16(3): 97544 Published online Mar 15, 2025. doi: 10.4239/wjd.v16.i3.97544
NR4A1 silencing alleviates high-glucose-stimulated HK-2 cells pyroptosis and fibrosis via hindering NLRP3 activation and PI3K/AKT pathway
Jin-Meng Li, Zi-Hua Song, Yuan Li, Han-Wen Chen, Han Li, Lu Yuan, Jing Li, Wen-Yue Lv, Lei Liu, Na Wang
Jin-Meng Li, Lu Yuan, Jing Li, Wen-Yue Lv, Department of Clinical Medicine, Jining Medical University, Jining 272013, Shandong Province, China
Zi-Hua Song, Yuan Li, Han-Wen Chen, Han Li, Lei Liu, Na Wang, Department of General Medicine, Affiliated Hospital of Jining Medical University, Jining 272029, Shandong Province, China
Co-corresponding authors: Lei Liu and Na Wang.
Author contributions: Liu L and Wang N contribute equally to this study as co-corresponding authors; Wang N and Liu L designed the research; Li JM, Song ZH, Chen HW, Li Y and Li H performed the research; Li JM, Li J, Yuan L and Lv WY analyzed the data and prepared the figures; Li JM and Wang N wrote the manuscript; Wang N and Liu L contributed to the review and revision of this manuscript; all authors have read and approved the final manuscript.
Supported by Research Fund for Academician Lin He New Medicine, No. JYHL2022FMS02.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Ethics Committee of Medical Science Research of the Affiliated Hospital of Jining Medical University (Approval No. 2023-10-B008).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: The original data can be obtained by contacting the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Na Wang, Doctor, Additional Professor, Department of General Medicine, Affiliated Hospital of Jining Medical University, No. 89 Guhuai Road, Jining 272029, Shandong Province, China. wangna19840906@163.com
Received: June 2, 2024 Revised: October 15, 2024 Accepted: December 16, 2024 Published online: March 15, 2025 Processing time: 233 Days and 4.4 Hours
Abstract
BACKGROUND
The pathophysiology of diabetic kidney disease (DKD) is complex. Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression. Previous studies have revealed that nuclear receptor subfamily 4 group A member 1 (NR4A1) may serve as a novel pathogenic element in DKD; however, the specific mechanism by which it contributes to pyroptosis and fibrosis in DKD is unknown.
AIM
To investigate the role of NR4A1 in renal pyroptosis and fibrosis in DKD and possible molecular mechanisms.
METHODS
Streptozotocin 60 mg/kg was injected intraperitoneally to establish a rat model of DKD. Typically, 45 mmol/L glucose [high glucose (HG)] was used to activate HK-2 cells to mimic the DKD model in vitro. HK-2 cells were transfected with NR4A1 siRNA to silence NR4A1.
RESULTS
NR4A1 was elevated in renal tissues of DKD rats and HG-stimulated HK-2 cells. Concurrently, NOD-like receptor protein 3 (NLRP3) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathways were triggered, and pyroptosis and expression of fibrosis-linked elements was increased in vivo and in vitro. These alterations were significantly reversed via NR4A1 silencing.
CONCLUSION
Inhibition of NR4A1 mitigated pyroptosis and fibrosis via suppressing NLRP3 activation and the PI3K/AKT pathway in HG-activated HK-2 cells.
Core Tip: This study demonstrated that nuclear receptor subfamily 4 group A member 1 (NR4A1) was upregulated in a rat model of diabetic kidney disease (DKD) and high-glucose-stimulated HK-2 cells. By transfecting siRNA of NR4A1, this study revealed that NR4A1 silencing attenuated DKD kidney pyroptosis and fibrosis in vitro. Mechanistically, silencing NR4A1 suppressed the activation of NOD-like receptor protein 3 and phosphoinositide 3-kinase/protein kinase B signaling pathways, which inhibited pyroptosis and fibrosis in vitro. These findings may provide a novel treatment strategy for patients with DKD.
