Tang JY, Chong YJ, Yang L, Li X, Yang Y, Li JC, Mu J. Activation of farnesoid X receptor upregulates binding immunoglobulin protein expression and alleviates diabetic nephropathy. World J Diabetes 2025; 16(8): 105228 [DOI: 10.4239/wjd.v16.i8.105228]
Corresponding Author of This Article
Jun-Chen Li, MD, Doctor, Department of Nephrology, University-Town Hospital of Chongqing Medical University, No. 55 Daxuecheng Middle Road, Shapingba District, Chongqing 401331, China. 8a3610@hospital.cqmu.edu.cn
Research Domain of This Article
Urology & Nephrology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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/
World J Diabetes. Aug 15, 2025; 16(8): 105228 Published online Aug 15, 2025. doi: 10.4239/wjd.v16.i8.105228
Activation of farnesoid X receptor upregulates binding immunoglobulin protein expression and alleviates diabetic nephropathy
Jian-Ying Tang, Yuan-Jia Chong, Lu Yang, Xue Li, Ying Yang, Jun-Chen Li, Jiao Mu
Jian-Ying Tang, Yuan-Jia Chong, Lu Yang, Xue Li, Ying Yang, Jun-Chen Li, Jiao Mu, Department of Nephrology, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China
Co-first authors: Jian-Ying Tang and Yuan-Jia Chong.
Co-corresponding authors: Jun-Chen Li and Jiao Mu.
Author contributions: Tang JY and Chong YJ wrote the manuscript and completed the figures; The data collection was completed by Li X, Yang L and Yang Y; The manuscript editing was completed by Li JC; Ideas were proposed by Mu J; All authors have read and approved the final manuscript.
Supported by the Talent Launch Fund of Chongqing Medical University Affiliated University City Hospital; and Chongqing Medical University Affiliated University City Hospital Youth Program, No. 2021ZD05.
Institutional review board statement: This study does not involve any human experiments.
Institutional animal care and use committee statement: The study protocol was approved by the ethical committee of the University-Town Hospital of Chongqing Medical University with approval No. LL-202127.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: Raw data used during the current study are available from the corresponding author on reasonable request for noncommercial use.
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: Jun-Chen Li, MD, Doctor, Department of Nephrology, University-Town Hospital of Chongqing Medical University, No. 55 Daxuecheng Middle Road, Shapingba District, Chongqing 401331, China. 8a3610@hospital.cqmu.edu.cn
Received: January 15, 2025 Revised: March 23, 2025 Accepted: June 11, 2025 Published online: August 15, 2025 Processing time: 211 Days and 10.4 Hours
Abstract
BACKGROUND
The exact mechanisms underlying diabetic nephropathy (DN) remain incompletely elucidated, prompting researchers to explore new perspectives and identify novel intervention targets in this field.
AIM
To explore the role and underlying mechanisms of farnesoid X receptor (FXR) in the development of DN by regulating endoplasmic reticulum stress (ERS) molecular chaperone binding immunoglobulin protein (BiP) expression.
METHODS
Bioinformatics analyses identified potential FXR-binding elements in the BiP promoter. Dual-luciferase and chromatin immunoprecipitation (ChIP) assays confirmed FXR-BiP binding sites. In vitro studies used SV40 MES 13 cells under varying glucose conditions and treatments with FXR modulators [obeticholic acid (INT-747) and guggulsterones] or BiP small interfering RNA. The expression of BiP and ERS-related proteins [protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6)] was assessed alongside cell proliferation and extracellular matrix (ECM) synthesis. In vivo studies in DN mice (db/db) examined the effects of FXR activation on renal function and morphology.
RESULTS
FXR bound to the target sequence in the BiP promoter region, enhancing transcriptional activity, as confirmed by ChIP experiments. FXR expression decreased in SV40 MES 13 cells stimulated with high glucose and in renal tissues of DN mice compared with control. Treatment of SV40 MES 13 cells with the FXR agonist INT-747 significantly increased intracellular BiP expression, whereas silencing the FXR gene led to the downregulation of BiP levels. In vivo administration of INT-747 significantly elevated BiP levels in renal tissues, improved renal function and fibrosis in DN mice, while inhibiting the expression of ERS-related signaling proteins PERK, IRE1, and ATF6.
CONCLUSION
FXR promotes BiP expression by binding to its promoter, suppressing ERS pathways, and reducing mesangial cell proliferation and ECM synthesis. These findings highlight FXR as a potential therapeutic target for diabetic glomerulosclerosis.
Core Tip: What was known: Farnesoid X receptor (FXR) agonists alleviate proteinuria and glomerulosclerosis in diabetic nephropathy mice by inhibiting inflammation and oxidative stress. Hence, their protective effects have become a research focus in recent years. However, the specific targets and signaling pathways involved in their regulation remain unclear. This study adds: We demonstrated for the first time that using bioinformatics prediction, protein immunoprecipitation, and luciferase reporter assays that FXR directly binds to the promoter region of the binding immunoglobulin protein (BiP) gene. FXR activates the transcriptional activity of BiP, thereby explaining the molecular mechanism of FXR-regulated BiP transcription. We confirmed through in vitro experiments that FXR agonist obeticholic acid (INT-747) administration significantly promotes BiP expression in high-glucose-induced SV40 MES13 cells, while FXR inhibitors downregulated BiP expression. Potential impact: FXR has a direct regulatory effect on BiP. This study provides valuable insights regarding the prevention and treatment of diabetic nephropathy.
