Activation of farnesoid X receptor upregulates binding immunoglobulin protein expression and alleviates diabetic nephropathy
Year: 2025
Type: article
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.
Source: World Journal of Diabetes
Authors: Jian-Ying Tang, Yuan-Jia Chong, Lu Yang, Xue Li, Ying Yang, Jun-Chen Li, Jiao Mu
Institution: Chongqing Medical University
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W4413969358