Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Apr 15, 2022; 13(4): 358-375
Published online Apr 15, 2022. doi: 10.4239/wjd.v13.i4.358
Long noncoding RNA X-inactive specific transcript regulates NLR family pyrin domain containing 3/caspase-1-mediated pyroptosis in diabetic nephropathy
Jia Xu, Qin Wang, Yi-Fan Song, Xiao-Hui Xu, He Zhu, Pei-Dan Chen, Ye-Ping Ren
Jia Xu, Qin Wang, Yi-Fan Song, Xiao-Hui Xu, He Zhu, Pei-Dan Chen, Ye-Ping Ren, Department of Nephrology, Shenzhen University General Hospital, Shenzhen 518000, Guangdong Province, China
Author contributions: Xu J, Wang Q, and Ren YP designed the research study; Song YF, Xu XH, Zhu H and Chen PD performed the research; Wang Q, Liang L and Xu XH analyzed the data and wrote the manuscript; all authors have read and approve the final manuscript.
Supported by Natural Science Foundation of Shenzhen University General Hospital (SUGH2020QD011).
Institutional animal care and use committee statement: All experiments and procedures were conducted following the laboratory animal care and use guidelines.
Conflict-of-interest statement: For this activity, the authors have no conflicts to declare.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
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: Ye-Ping Ren, PhD, Chief Doctor, Department of Nephrology, Shenzhen University General Hospital, No. 1098 Xueyuan Road, Nanshan District, Shenzhen 518000, Guangdong Province, China. drrenyeping123@163.com
Received: October 15, 2021
Peer-review started: October 15, 2021
First decision: December 27, 2021
Revised: January 24, 2022
Accepted: March 15, 2022
Article in press: March 15, 2022
Published online: April 15, 2022
ARTICLE HIGHLIGHTS
Research background

Diabetes is a metabolic disease characterized by hyperglycemia. Chronic hyperglycemia can lead to chronic damage and dysfunction of various tissues and organs, such as eyes, kidneys, heart, blood vessels, and nerves. Various complications caused by diabetes are unavoidable problems in the treatment of diabetes mellitus, including diabetic nephropathy (DN). Understanding the molecular regulation mechanism of DN during renal injury is helpful to the treatment of DN.

Research motivation

Cell pyroptosis is a programmed cell death pattern and plays a key role in DN. However, the regulation mechanism of cell pyroptosis in DN has not been studied clearly. Therefore, our research will help to reveal the role of cell pyroptosis in DN.

Research objectives

Long noncoding RNA X inactive specific transcript (LncRNA XIST) was taken as the main object of our research to explore the molecular mechanism of XIST in pyroptosis of renal tubular epithelial cells (RTECs). We found that XIST comparatively bound to microRNA (miR)-15b-5p to regulate Toll like receptor 4 (TLR4) expression and promote RTEC pyroptosis to participate in kidney injury in DN. Our research results provide a new theoretical basis for the treatment of DN.

Research methods

To study the mechanism of XIST in the pathogenesis of DN-induced pyroptosis, we established DN rat models and high glucose (HG)-induced cell models. By detecting and intervening in the expression of XIST in animal models and cell models, we observed the pathological and representational changes of the models, and collected and analyzed the experimental data. Our research methods conform to science and are carried out strict experimental operation according to the experimental principle, and the results are representative.

Research results

Through experiments, we found that lncRNA XIST was highly expressed in the DN models, and XIST increased the expression of TLR4 as a competing endogenous RNA by competing with miR-15-5p. Inhibiting the expression of XIST repressed the expression of TLR4 by upregulating miR-15-5p, and effectively improved the pyroptosis of RTECs induced by DN. Our findings explain the regulatory mechanism of lncRNA XIST in the pathogenesis of DN-induced RTEC pyroptosis. However, our results have not yet been clinically validated and further exploration is warranted in clinical transformation.

Research conclusions

This study for the first time revealed that lncRNA XIST can enhance the expression of TLR4 through competitively binding to miR-15-5p and promote the pyroptosis of RTECs induced by DN. No new methods were used during the study.

Research perspectives

In the future, we will explore more mechanisms for other targeted miRNAs in the downstream of lncRNA XIST, and we will also study the clinical transformation of XIST/miR-15-5p/TLR4 in DN.