Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Mar 15, 2024; 15(3): 502-518
Published online Mar 15, 2024. doi: 10.4239/wjd.v15.i3.502
Jianpi Gushen Huayu decoction ameliorated diabetic nephropathy through modulating metabolites in kidney, and inhibiting TLR4/NF-κB/NLRP3 and JNK/P38 pathways
Zi-Ang Ma, Li-Xin Wang, Hui Zhang, Han-Zhou Li, Li Dong, Qing-Hai Wang, Yuan-Song Wang, Bao-Chao Pan, Shu-Fang Zhang, Huan-Tian Cui, Shu-Quan Lv
Zi-Ang Ma, Graduate School, Hebei University of Chinese Medicine, Shijiazhuang 050000, Hebei Province, China
Li-Xin Wang, Hui Zhang, Li Dong, Qing-Hai Wang, Yuan-Song Wang, Bao-Chao Pan, Shu-Fang Zhang, Department of Endocrinology, Cangzhou Hospital of Integrated Traditional Chinese Medicine and Western Medicine of Hebei Province Affiliated to Hebei University of Chinese Medicine, Cangzhou 061000, Hebei Province, China
Han-Zhou Li, School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300000, China
Huan-Tian Cui, The First School of Clinical Medicine, Yunnan University of Traditional Chinese Medicine, Kunming 065000, Yunnan Province, China
Shu-Quan Lv, Department of Endocrinology, Hebei Cangzhou Hospital of Integrative Medicine, Cangzhou 061000, Hebei Province, China
Author contributions: Cui HT and Lv SQ conceived and designed the study; Ma ZA, Wang LX, Zhang H, and Li HZ conducted the experiments and obtained the data; Li HZ, Dong L, and Wang QH analyzed and collated the data; Ma ZA, Wang YS, and Pan BC drafted and written the final version of the manuscript; Zhang SF, Cui HT, and Lv SQ contributed equally to this work; and all authors approved the final version of the manuscript.
Supported by the Scientific Foundation of Administration of Traditional Chinese Medicine of Hebei Province, China, No. 2023257.
Institutional animal care and use committee statement: The animal study was reviewed and approved by Ethics Committee of Hebei University of Chinese Medicine (Approval No. CZX2021-KY-026).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.
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: Shu-Quan Lv, Doctor, Chief Physician, Department of Endocrinology, Hebei Cangzhou Hospital of Integrative Medicine, No. 31 Huanghe Road, Cangzhou 061000, Hebei Province, China. czlvshuquan@163.com
Received: September 24, 2023
Peer-review started: September 24, 2023
First decision: November 30, 2023
Revised: December 21, 2023
Accepted: January 30, 2024
Article in press: January 30, 2024
Published online: March 15, 2024
Processing time: 173 Days and 2.4 Hours
Abstract
BACKGROUND

Jianpi Gushen Huayu Decoction (JPGS) has been used to clinically treat diabetic nephropathy (DN) for many years. However, the protective mechanism of JPGS in treating DN remains unclear.

AIM

To evaluate the therapeutic effects and the possible mechanism of JPGS on DN.

METHODS

We first evaluated the therapeutic potential of JPGS on a DN mouse model. We then investigated the effect of JPGS on the renal metabolite levels of DN mice using non-targeted metabolomics. Furthermore, we examined the effects of JPGS on c-Jun N-terminal kinase (JNK)/P38-mediated apoptosis and the inflammatory responses mediated by toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3).

RESULTS

The ameliorative effects of JPGS on DN mice included the alleviation of renal injury and the control of inflammation and oxidative stress. Untargeted metabolomic analysis revealed that JPGS altered the metabolites of the kidneys in DN mice. A total of 51 differential metabolites were screened. Pathway analysis results indicated that nine pathways significantly changed between the control and model groups, while six pathways significantly altered between the model and JPGS groups. Pathways related to cysteine and methionine metabolism; alanine, tryptophan metabolism; aspartate and glutamate metabolism; and riboflavin metabolism were identified as the key pathways through which JPGS affects DN. Further experimental validation showed that JPGS treatment reduced the expression of TLR4/NF-κB/NLRP3 pathways and JNK/P38 pathway-mediated apoptosis related factors.

CONCLUSION

JPGS could markedly treat mice with streptozotocin (STZ)-induced DN, which is possibly related to the regulation of several metabolic pathways found in kidneys. Furthermore, JPGS could improve kidney inflammatory responses and ameliorate kidney injuries in DN mice via the TLR4/NF-κB/NLRP3 pathway and inhibit JNK/P38 pathway-mediated apoptosis in DN mice.

Keywords: Diabetic nephropathy; Jianpi Gushen Huayu Decoction; Oxidative stress; Inflammation; Untargeted metabolomics; Toll-like receptor 4/nuclear factor-kappa B/NOD-like receptor family pyrin domain containing 3 pathway; c-Jun N-terminal kinase/P38-mediated apoptosis

Core Tip: Traditional Chinese medicine (TCM) has been demonstrated to possess beneficial effects on diabetes and its complications. Elucidating upon these mechanisms can contribute to the modernization of TCM. The dysfunction of metabolism is closely related to the progression of diabetes and diabetic complications. Using untargeted metabolomics can be useful in studying the metabolic regulatory mechanisms of TCM. The current study used untargeted metabolomics to evaluate the differential metabolites in a diabetic nephropathy (DN) mouse model after Jianpi Gushen Huayu Decoction (JPGS) treatment. Moreover, we deeply analyzed the results from metabolomics and tested the potential pathways related to the differential metabolites. Our results revealed that JPGS could markedly treat mice with streptozotocin (STZ)-induced DN. The metabolomics results exhibited that the efficacy of JPGS is possibly related to cysteine and methionine metabolism; alanine, aspartate, and glutamate metabolism; tryptophan metabolism; and riboflavin metabolism.