Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Aug 15, 2022; 13(8): 600-612
Published online Aug 15, 2022. doi: 10.4239/wjd.v13.i8.600
Clopidogrel delays and can reverse diabetic nephropathy pathogenesis in type 2 diabetic db/db mice
Hong-Qin Li, Nian Liu, Zong-Yu Zheng, Hao-Lin Teng, Jin Pei
Hong-Qin Li, Jin Pei, Department of Biopharmacy, Jilin University School of Pharmaceutical Sciences, Changchun 130021, Jilin Province, China
Hong-Qin Li, Nian Liu, Zong-Yu Zheng, Hao-Lin Teng, Department of Urology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
Author contributions: Pei J and Li HQ contributed to conception and design of the study; Li HQ and Liu N performed the experiment; Zheng ZY organized the database; Teng HL performed the statistical analysis; Li HQ and Liu N wrote the draft of the manuscript; and all authors contributed to manuscript revision, read, and approved the submitted version.
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
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: Jin Pei, PhD, Professor, Department of Biopharmacy, Jilin University School of Pharmaceutical Sciences, No. 1163, Xinmin street, Changchun 130021, Jilin Province, China. peijin@jlu.edu.cn
Received: October 18, 2021
Peer-review started: October 18, 2021
First decision: December 27, 2021
Revised: January 26, 2022
Accepted: June 27, 2022
Article in press: June 27, 2022
Published online: August 15, 2022
Processing time: 298 Days and 4.6 Hours
Abstract
BACKGROUND

Diabetic nephropathy (DN) is the principal cause of end-stage renal disease. Previous studies have shown that clopidogrel can prevent the early progression of renal injury.

AIM

To elucidate whether clopidogrel is beneficial against DN by using a db/db mouse model.

METHODS

db/db mice with a higher urinary albumin/creatinine ratio (ACR) relative to age- and sex-matched wild-type control mice were randomly allocated to clopidogrel and vehicle treatment groups. Clopidogrel was administered at doses of 5, 10, and 20 mg/kg by gavage for 12 wk. Body mass, blood glucose level, and urinary creatinine and albumin concentrations in each group were measured before and after the intervention. Renal fibrosis was evaluated using periodic acid-Schiff and Masson’s trichrome staining. The renal protein expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and F4/80 was assessed using immunohistochemistry. Urinary TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-6 levels were analyzed using enzyme-linked immunosorbent assay; TNF-α and IL-1β mRNA expression was measured using real-time quantitative polymerase chain reaction. The protein expression of fibronectin (FN) and collagen I was assessed using immunohistochemistry.

RESULTS

Clopidogrel treatment did not affect the body mass or blood glucose level of the db/db mice; however, it increased bleeding time and reduced urinary ACR in a dose-dependent manner. Immunohistochemical staining revealed an amelioration of renal fibrosis, significantly lower deposition of FN and collagen I, and significantly lower expression of the proinflammatory cytokines TNF-α and IL-1β and lower levels of urinary TNF-α and MCP-1 in the clopidogrel-treated db/db mice (P < 0.05). Furthermore, clopidogrel significantly reduced macrophage infiltration into the glomeruli of the db/db mice.

CONCLUSION

Clopidogrel significantly reduced renal collagen deposition and fibrosis and prevented renal dysfunction in db/db mice, most likely through inhibition of renal macrophage infiltration and the associated inflammation.

Keywords: Diabetes; Clopidogrel; Inflammation; Fibronectin; Diabetic nephropathy

Core Tip: Diabetic nephropathy is the most common microvascular inflammatory disease among the diabetic complications. Previous studies have shown that clopidogrel administration is an effective means of suppressing inflammation in diseases such as acute myocardial infarction, diabetes, and acute ischemic cerebral infarction. In this study, we aimed to determine whether treatment with clopidogrel has a preventive or therapeutic effect in the kidneys of obese, type 2 diabetic db/db mice. In this experiment, we demonstrated that clopidogrel significantly reduced renal collagen deposition and fibrosis and prevented renal dysfunction in db/db mice, most likely through inhibition of renal macrophage infiltration and the associated inflammation.