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
Processing time: 97 Days and 21.1 Hours
ARTICLE HIGHLIGHTS
Research background

Diabetic nephropathy (DN) is frequently observed as a chronic microvascular complication linked to end-stage renal disease, and it constitutes a significant contributor to both disability and mortality worldwide. Current therapies merely delay renal injury by controlling metabolic disturbances that occur in the early stage and, as such, there remains an urgent need to seek out and develop new drugs for clinical use. To this end, we have performed focused research on the Chinese patent medicine Abelmoschus manihot for its ability to decrease proteinuria in patients with DN.

Research motivation

Previous studies have indicated that myricetin possesses the potential to mitigate the pathological alterations observed in renal tissues of DN patients and models. Nevertheless, the precise molecular mechanism through which myricetin influences the progression of DN remains uncertain.

Research objectives

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

Research methods

Db/db diabetic mice were administered myricetin and effects on blood and urine indexes and renal tissue pathology were assessed. Additionally, the RAW 264.7 cell line was cultured in high glucose conditions and then exposed to the PI3K/Akt inhibitor LY294002. In both the in vivo and in vitro settings, quantification of various inflammation factors’ levels was conducted using western blotting, real-time qPCR and ELISA.

Research results

In the db/db mice, myricetin had a mitigating effect on renal dysfunction and fibrosis, including kidney injury markers kidney injury molecule-1 and neutrophil gelatinase associated lipocalin and inflammatory cytokine-related factors. In the RAW 264.7 cells, myricetin treatment effectively inhibited the up-regulation of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1β and modulated M1-type polarization. Molecular docking and bioinformatic analyses revealed that Akt was 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.

Research conclusions

Myricetin effectively mitigates kidney injury in DN mice through the regulation of macrophage polarization via the PI3K/Akt signaling pathway.

Research perspectives

Myricetin represents a promising therapy in treating DN.