Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Jan 15, 2024; 15(1): 105-125
Published online Jan 15, 2024. doi: 10.4239/wjd.v15.i1.105
Myricetin induces M2 macrophage polarization to alleviate renal tubulointerstitial fibrosis in diabetic nephropathy via PI3K/Akt pathway
Wei-Long Xu, Pei-Pei Zhou, Xu Yu, Ting Tian, Jin-Jing Bao, Chang-Rong Ni, Min Zha, Xiao Wu, Jiang-Yi Yu
Wei-Long Xu, Pei-Pei Zhou, Xu Yu, Ting Tian, Jin-Jing Bao, Min Zha, Jiang-Yi Yu, Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
Chang-Rong Ni, Department of Pharmacy, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
Xiao Wu, Department of Pneumology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
Co-first authors: Wei-Long Xu and Pei-Pei Zhou.
Co-corresponding authors: Xiao Wu and Jiang-Yi Yu.
Author contributions: Xu WL and Yu JY designed the study; Xu WL and Zhou PP carried out the experiments; Tian T, Yu X, and Bao JJ contributed experiment assistance; Yu X, Bao JJ, and Zha M analyzed the data; Xu WL and Zhou PP generated the figures; Ni CR donated the myricetin natural product; Xu WL, Zhou PP, Yu JY, and Wu X drafted and revised the manuscript; Yu JY and Wu X conceived and supervised the study; All authors approved the final version of the article. Xu WL and Zhou PP contributed equally to this work as co-first authors. Xu WL and Zhou PP together completed the chief experiments, formation of figures, and writing of initial manuscript, which were the most important and indispensable part of this study. Especially, Xu WL designed the study. Yu JY and Wu X contributed equally to this work as co-corresponding authors. Yu JY and Wu X revised the manuscript, conceived and supervised the study to make the study better presented. Especially, Yu JY provided enough financial support in the progress of experiments and ensured all the journal’s administrative requirements.
Supported by National Natural Science Foundation of China, No. 82205025, No. 82374355 and No. 82174293; Subject of Jiangsu Province Hospital of Chinese Medicine, No. Y21023; and Forth Batch of Construction Program for Inheritance Office of Jiangsu Province Famous TCM Experts, No. [2021]7.
Institutional animal care and use committee statement: Pathogen-free environments and ad libitum feeding were ensured for all animals. In accordance with its Ethics Committee, Jiangsu Province Hospital of Chinese Medicine approved the procedures for care and use of animals [QK-20200408-001]. Full compliance with all applicable institutional and governmental regulations regarding animal ethics was maintained throughout the study.
Conflict-of-interest statement: The authors declare that there were no commercial nor financial relationships that could be considered as potential conflicts of interest in the research.
Data sharing statement: The raw data are available upon reasonable request from the corresponding author.
ARRIVE guidelines statement: The authors have read and 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: Jiang-Yi Yu, MD, Chief Doctor, Chief Physician, Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155 Hanzhong Road, Qinhuai District, Nanjing 210000, Jiangsu Province, China. yujiangyi2007@163.com
Received: October 6, 2023
Peer-review started: October 6, 2023
First decision: November 14, 2023
Revised: November 28, 2023
Accepted: December 15, 2023
Article in press: December 15, 2023
Published online: January 15, 2024
Abstract
BACKGROUND

Development of end-stage renal disease is predominantly attributed to diabetic nephropathy (DN). Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissue. Nevertheless, the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain.

AIM

To investigate the effects of myricetin on DN and explore its potential therapeutic mechanism.

METHODS

Db/db mice were administered myricetin intragastrically on a daily basis at doses of 50 mg/kg or 100 mg/kg for a duration of 12 wk. Subsequently, blood and urine indexes were assessed, along with examination of renal tissue pathology. Kidney morphology and fibrosis were evaluated using various staining techniques including hematoxylin and eosin, periodic acid–Schiff, Masson’s trichrome, and Sirius-red. Additionally, high-glucose culturing was conducted on the RAW 264.7 cell line, treated with 25 mM myricetin or co-administered with the PI3K/Akt inhibitor LY294002 for a period of 24 h. In both in vivo and in vitro settings, quantification of inflammation factor levels was conducted using western blotting, real-time qPCR and ELISA.

RESULTS

In db/db mice, administration of myricetin led to a mitigating effect on DN-induced renal dysfunction and fibrosis. Notably, we observed a significant reduction in expressions of the kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin, along with a decrease in expressions of inflammatory cytokine-related factors. Furthermore, myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha, interleukin-6, and interluekin-1β induced by high glucose in RAW 264.7 cells. Additionally, myricetin modulated the M1-type polarization of the RAW 264.7 cells. Molecular docking and bioinformatic analyses revealed Akt as the target of myricetin. The protective effect of myricetin was nullified upon blocking the polarization of RAW 264.7 via inhibition of PI3K/Akt activation using LY294002.

CONCLUSION

This study demonstrated that myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.

Keywords: Myricetin, Diabetic nephropathy, PI3K/Akt pathway, Renal tubulointerstitial fibrosis, Macrophage, Polarization

Core Tip: Myricetin, a flavonoid, has been extensively utilized in the domains of anti-inflammatory and anti-cancer research. However, the precise mechanism by which myricetin influences the onset and development of diabetic nephropathy (DN) remains a mystery. To address this knowledge gap, we conducted a study wherein we induced DN in db/db mice and subsequently administered myricetin as a treatment. Our findings demonstrated that high concentrations of myricetin effectively mitigated renal injury, inflammation, fibrosis, and other related factors in DN mice. Furthermore, we conducted in vitro experiments to confirm that myricetin activated the PI3K/Akt signaling pathway, thereby inhibiting the polarity shift of macrophages.