Farnesoid X receptor activation protects against renal fibrosis via modulation of β-catenin signaling
Farnesoid X receptor activation protects against renal fibrosis via modulation of β-catenin signaling
Objective: activation of farnesoid X receptor (FXR), a bile acid nuclear receptor, may be implicated in the pathophysiology of diabetic nephropathy. We explored a possible role for FXR activation in preventing renal fibrosis in high fat diet (HFD)-fed mice.
Methods: we investigated the effects of HFD on mouse kidney and renal tubular epithelial cells both in vivo and in vitro, and observed the changes of FXR and β8 catenin pathway. FXR agonist was also used to alleviate this HFD-induced effect, and the interaction between FXR and β-catenin was further verified.
Results: mice fed a 60% kcal fat diet for 20 weeks developed the typical traits of
metabolic syndrome with subsequent renal lipid accumulation and renal injury. Treatment with the FXR agonist CDCA or GW4064 decreased body weight, renal lipid accumulation, as well as renal injury. Moreover, renal β-catenin signaling was activated and improved with FXR-agonist treatment in HFD-fed mice. To examine whether FXR affected β-catenin signaling, and was involved in tubulo-interstitial fibrosis, we explored the FXR expression and function in ox-LDL induced-renal tubular injury. In rat proximal tubular epithelial cells (NRK-52E) stimulated by ox18 LDL, FXR protein was decreased compared to control group, and phosphorylated (Ser675) β-catenin was activated by ox-LDL in a dose- and time-dependent manner. Ox-LDL enhanced α-SMA and fibronectin expressions and reduced E-cadherin levels, whereas FXR agonism or FXR overexpression inhibited fibronectin and α-SMA expressions and restored E-cadherin. Moreover, FXR agonist treatment also decreased phosphorylated (Ser675) β-catenin, nuclear translocation and β-catenin-mediated transcription induced by ox-LDL in NRK-52E cells. We showed that FXR could bind with β-catenin via the AF1 domain, and disrupt the assembly of the core β4 catenin/TCF4 complex.
Conclusion: these experimental data suggest that FXR activation, via modulating β-catenin signaling, may contribute to attenuating the development of lipid-mediated tubulo-interstitial fibrosis.
Bile acid, FXR, Renal fibrosis, Tubular epithelial cells, β-Catenin
Sun, Dan-Qin
56d2d368-71df-400a-8a1d-a62afdce5771
Yuan, Fuqiang
3ae656b8-65ac-44ee-9134-dd006bbda0c3
Fu, Meng-Zhu
04f6194b-c98a-4d6f-900e-46f4f1ab3793
Zhong, Meng-Yang
fbaa5df3-bb48-4da4-b5c8-d5b4bd3a1ba3
Zhang, Shi-Liang
5287f931-fb15-4c4c-9b17-be923c178657
Lu, Yan
096fe3e5-476c-46cd-bfb5-b237912f02b5
Targher, Giovanni
984048f3-f465-4a7a-b0c9-7a7064ab45a8
Byrne, Christopher D.
1370b997-cead-4229-83a7-53301ed2a43c
Zheng, Ming-Hua
100ad35f-df13-47d5-adec-18fb9dfdd189
Yuan, Wei-Jie
5c291a54-a354-4b77-836a-13449792d756
8 December 2023
Sun, Dan-Qin
56d2d368-71df-400a-8a1d-a62afdce5771
Yuan, Fuqiang
3ae656b8-65ac-44ee-9134-dd006bbda0c3
Fu, Meng-Zhu
04f6194b-c98a-4d6f-900e-46f4f1ab3793
Zhong, Meng-Yang
fbaa5df3-bb48-4da4-b5c8-d5b4bd3a1ba3
Zhang, Shi-Liang
5287f931-fb15-4c4c-9b17-be923c178657
Lu, Yan
096fe3e5-476c-46cd-bfb5-b237912f02b5
Targher, Giovanni
984048f3-f465-4a7a-b0c9-7a7064ab45a8
Byrne, Christopher D.
1370b997-cead-4229-83a7-53301ed2a43c
Zheng, Ming-Hua
100ad35f-df13-47d5-adec-18fb9dfdd189
Yuan, Wei-Jie
5c291a54-a354-4b77-836a-13449792d756
Sun, Dan-Qin, Yuan, Fuqiang, Fu, Meng-Zhu, Zhong, Meng-Yang, Zhang, Shi-Liang, Lu, Yan, Targher, Giovanni, Byrne, Christopher D., Zheng, Ming-Hua and Yuan, Wei-Jie
(2023)
Farnesoid X receptor activation protects against renal fibrosis via modulation of β-catenin signaling.
Molecular Metabolism, 79, [101841].
(doi:10.1016/j.molmet.2023.101841).
Abstract
Objective: activation of farnesoid X receptor (FXR), a bile acid nuclear receptor, may be implicated in the pathophysiology of diabetic nephropathy. We explored a possible role for FXR activation in preventing renal fibrosis in high fat diet (HFD)-fed mice.
Methods: we investigated the effects of HFD on mouse kidney and renal tubular epithelial cells both in vivo and in vitro, and observed the changes of FXR and β8 catenin pathway. FXR agonist was also used to alleviate this HFD-induced effect, and the interaction between FXR and β-catenin was further verified.
Results: mice fed a 60% kcal fat diet for 20 weeks developed the typical traits of
metabolic syndrome with subsequent renal lipid accumulation and renal injury. Treatment with the FXR agonist CDCA or GW4064 decreased body weight, renal lipid accumulation, as well as renal injury. Moreover, renal β-catenin signaling was activated and improved with FXR-agonist treatment in HFD-fed mice. To examine whether FXR affected β-catenin signaling, and was involved in tubulo-interstitial fibrosis, we explored the FXR expression and function in ox-LDL induced-renal tubular injury. In rat proximal tubular epithelial cells (NRK-52E) stimulated by ox18 LDL, FXR protein was decreased compared to control group, and phosphorylated (Ser675) β-catenin was activated by ox-LDL in a dose- and time-dependent manner. Ox-LDL enhanced α-SMA and fibronectin expressions and reduced E-cadherin levels, whereas FXR agonism or FXR overexpression inhibited fibronectin and α-SMA expressions and restored E-cadherin. Moreover, FXR agonist treatment also decreased phosphorylated (Ser675) β-catenin, nuclear translocation and β-catenin-mediated transcription induced by ox-LDL in NRK-52E cells. We showed that FXR could bind with β-catenin via the AF1 domain, and disrupt the assembly of the core β4 catenin/TCF4 complex.
Conclusion: these experimental data suggest that FXR activation, via modulating β-catenin signaling, may contribute to attenuating the development of lipid-mediated tubulo-interstitial fibrosis.
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Accepted/In Press date: 22 November 2023
e-pub ahead of print date: 28 November 2023
Published date: 8 December 2023
Additional Information:
Funding Information:
This work was supported by grants from the National Natural Science Foundation of China ( 81970624 , 82000690 ), China Postdoctoral Science Foundation ( 2023M732681 ), Top-notch Talents from Young and Middle-Age Health Care in Wuxi ( BJ2020026 ), Youth Research Project Fund from Wuxi Municipal Health Commission ( Q201932 ) and Technology Development Fund in Wuxi ( N20202001 ). GT was supported in part by grants from the School of Medicine, University of Verona , Italy. CDB was supported in part by the Southampton NIHR Biomedical Research Centre (NIHR 203319 ), UK.
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© 2023 The Authors
Keywords:
Bile acid, FXR, Renal fibrosis, Tubular epithelial cells, β-Catenin
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Local EPrints ID: 484850
URI: http://eprints.soton.ac.uk/id/eprint/484850
PURE UUID: 3c21fc5a-f7ca-4a2c-8d26-b7d5c2c4e804
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Date deposited: 23 Nov 2023 17:32
Last modified: 18 Mar 2024 02:50
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Author:
Dan-Qin Sun
Author:
Fuqiang Yuan
Author:
Meng-Zhu Fu
Author:
Meng-Yang Zhong
Author:
Shi-Liang Zhang
Author:
Yan Lu
Author:
Giovanni Targher
Author:
Ming-Hua Zheng
Author:
Wei-Jie Yuan
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