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Activation of farnesoid X receptor upregulates binding immunoglobulin protein expression and alleviates diabetic
Jian-Ying Tang1, Yuan-Jia Chong1, Lu Yang1
1Department of Nephrology, University-Town Hospital of Chongqing Medical University, Chongqing 401331, China.
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.
Insights
Farnesoid X receptor (FXR) activation promotes binding immunoglobulin protein (BiP) expression, suppressing endoplasmic reticulum stress (ERS) pathways. This research identifies FXR as a potential therapeutic target for diabetic nephropathy (DN).
Area of Science:
- Endocrinology and Metabolism
- Nephrology
- Molecular Biology
Background:
- Diabetic nephropathy (DN) mechanisms are not fully understood.
- Novel therapeutic targets for DN are needed.
Purpose of the Study:
- Investigate the role of farnesoid X receptor (FXR) in DN.
- Elucidate FXR's mechanism in regulating endoplasmic reticulum stress (ERS) via binding immunoglobulin protein (BiP) expression.
Main Methods:
- Bioinformatics and molecular assays (dual-luciferase, ChIP) to confirm FXR-BiP interaction.
- In vitro studies with cell lines under high glucose and FXR modulators.
- In vivo studies in diabetic nephropathy (DN) mice (db/db) to assess renal function and morphology.
Main Results:
- FXR binds to the BiP promoter, enhancing its transcription.
- FXR expression is reduced in high glucose conditions and in DN.
- FXR activation (INT-747) increases BiP, improves renal function, and reduces fibrosis in DN mice, while inhibiting ERS signaling proteins.
Conclusions:
- FXR promotes BiP expression, suppresses ERS, and reduces mesangial cell proliferation and ECM synthesis.
- FXR is a potential therapeutic target for diabetic glomerulosclerosis.
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