Copyright
©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Metformin regulates inflammation and fibrosis in diabetic kidney disease through TNC/TLR4/NF-κB/miR-155-5p inflammatory loop
Yang Zhou, Xiao-Yu Ma, Jin-Yu Han, Min Yang, Chuan Lv, Ying Shao, Yi-Li Wang, Jia-Yi Kang, Qiu-Yue Wang
Yang Zhou, Yi-Li Wang, Jia-Yi Kang, Qiu-Yue Wang, Department of Endocrinology, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
Xiao-Yu Ma, Jin-Yu Han, Department of Gerontology, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
Min Yang, Department of Clinical Laboratory, The First Affiliated Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
Chuan Lv, Department of Endocrinology, The People’s Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
Ying Shao, Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang 110000, Liaoning Province, China
Author contributions: Zhou Y performed the experiments and data analysis and contributed to paper writing; Ma XY performed the experiments and data analysis; Han JY, Yang M, and Lv C performed the experiments; Shao Y supervised the project and contributed to paper writing; Wang YL contributed to paper writing; Kang JY performed the data analysis and contributed to paper writing; Wang QY supervised the project, finalized the manuscript, and managed the submission process.
Supported by National Key Research and Development Program of China, No. 2018YFC1313900 and No. 2018YFC1313901; and The Higher School High-end Talent Team Construction of Liaoning Province, No. [2014]187.
Institutional review board statement: This study was approved by The Ethics Committee of The First Affiliated Hospital of China Medical University. All procedures were performed in accordance with the ethical standards mentioned in the 1964 Declaration of Helsinki and its subsequent amendments or comparable ethical standards.
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals. All experiments were approved by The Institutional Animal Care and Use Committee (IACUC) of The China Medical University Animal Experiment Department, Approval No. 2017112.
Conflict-of-interest statement: The author(s) have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article 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:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Qiu-Yue Wang, PhD, Professor, Department of Endocrinology, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang 110000, Liaoning Province, China.
wqycmu123@163.com
Received: August 21, 2020
Peer-review started: August 21, 2020
First decision: September 21, 2020
Revised: October 5, 2020
Accepted: October 26, 2020
Article in press: October 26, 2020
Published online: January 15, 2021
Processing time: 138 Days and 23.6 Hours
ARTICLE HIGHLIGHTS
Research background
With the increasing incidence of diabetes, the incidence of diabetic kidney disease (DKD) continues to rise, which has become the leading cause of end-stage renal disease. However, current treatments like angiotensin-converting enzyme inhibitors only partially inhibited the DKD progression. Thus, the mechanisms underlying DKD should be clarified and disclosed, and new strategies for delaying the progression are urgently needed.
Research motivation
By testing the serum tenascin-C (TNC) level in patients with type 2 diabetic mellitus (T2DM), we aim to provide insights into the pathogenesis of the DKD and suggest that TNC can serve as a therapeutic target for this disease.
Research objectives
In the present study, we evaluated the alterations of TNC expression levels in the serum or/and glomeruli of patients with T2DM and rats with streptozotocin-induced diabetes. We also evaluated the diagnose indexes of DKD, including glycosylated hemoglobin (HbA1c) level, body mass index (BMI), systolic blood pressure (SBP), and urinary albumin to creatinine ratio (UACR) in the serum of patients. In addition, we explored the specific molecular mechanism of TNC on DKD by culturing rat glomerular mesangial cells.
Research methods
Diabetes patient serum samples were collected to detect the expression level of TNC in serum and make analysis with other related factors in diabetes. Diabetic rat models were used to observe the expression of TNC in diabetic rat kidney, and enzyme-linked immunosorbent assay was used to detect the expression of TNC in diabetic rat serum, and analyze the associated renal function indexes. SiRNA transfection technique was used in cultured rat glomerular mesangial cells stimulated with high glucose to explore the molecular mechanisms of TNC in DKD.
Research results
Diabetic patients had significantly increased serum levels of TNC, and TNC was positively correlated with UACR, BMI, SBP, and DBP. TNC expression in diabetic rat kidney increased obviously, and diabetic rats had significantly higher serum TNC expression levels compared with normal rats. Urea nitrogen and creatinine were positively correlated with the increase of TNC in diabetic rats. Rat glomerular mesangial cells stimulated with high glucose had significantly increased protein expression of TNC, and TNC can promote inflammation and fibrosis through the Toll-like receptor 4/nuclear factor-κB pathway. Metformin can inhibit the expression of TNC and delay the progress of DKD.
Research conclusions
We demonstrated that increased TNC expression is involved in the cascade of DKD. Importantly, inhibition of TNC delays the development of DKD, indicating that TNC represents a potential therapeutic target in DKD.
Research perspectives
By targeting TNC expression, the occurrence and development of DKD can be delayed.
