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Urantide alleviates atherosclerosis-related liver and kidney injury via the Wnt/β-catenin signaling pathway in ApoE(−/−) mice

Urantid lindert arteriosklerosebedingte Leber- und Nierenschädigungen über den Wnt/β-Catenin-Signalweg bei ApoE(−/−)-Mäusen

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Abstract

Objective

To investigate the role of urantide in the prevention and treatment of atherosclerosis (AS)-related liver and kidney injury by antagonizing the urotensin II/urotensin receptor (UII/UT) system and regulating the Wnt/β-catenin signaling pathway.

Methods

Atherosclerotic ApoE−/− mice were treated with 20 mg/kg, 30 mg/kg, and 40 mg/kg urantide for 14 days.

Results

When ApoE−/− mice developed AS, significant pathological changes occurred in the liver and kidney, and the UII/UT system in tissue was highly activated; furthermore, the Wnt/β-catenin signalling pathway was activated, and proteins related to this signalling pathway, such as GSK-3β, AXIN2, CK‑1, and APC, were significantly downregulated. After urantide treatment, the pathological damage to the liver and kidney was effectively improved, the activity of the UII/UT system was effectively inhibited, and the expression of the Wnt/β-catenin signalling pathway and related proteins was restored. Wnt/β-catenin signals were mainly localized in the cytoplasm, renal tubules, and interstitium.

Conclusion

Urantide could improve AS-related liver and kidney injury by antagonizing the UII/UT system, and the improvements in liver and kidney function in atherosclerotic ApoE−/− mice may be related to inhibition of the Wnt/β-catenin signalling pathway.

Zusammenfassung

Zielsetzung

Untersuchung der Rolle von Urantid bei der Vorbeugung und Behandlung von Arteriosklerose (AS)-bedingten Leber- und Nierenschäden durch Antagonisierung des Urotensin II/Urotensin-Rezeptor(UII/UT)-Systems und Regulierung des Wnt/β-Catenin-Signalwegs.

Methoden

Arteriosklerotische ApoE(−/−)-Mäuse wurden 14 Tage lang mit 20 mg/kg, 30 mg/kg bzw. 40 mg/kg Urantid behandelt.

Ergebnisse

Als ApoE(−/−)-Mäuse eine Arteriosklerose entwickelten, traten signifikante pathologische Veränderungen in der Leber und Niere auf, und das UII/UT-System im Gewebe war stark aktiviert; außerdem war der Wnt/β-Catenin-Signalweg aktiviert, und Proteine, die mit diesem Signalweg in Verbindung stehen, wie GSK-3β, AXIN2, CK‑1 und APC, waren signifikant herunterreguliert. Nach der Behandlung mit Urantid wurden die pathologischen Schäden an Leber und Niere effektiv verbessert, die Aktivität des UII/UT-Systems wurde effektiv gehemmt, und die Expression des Wnt/β-Catenin-Signalwegs und der damit verbundenen Proteine wurde wiederhergestellt. Die Wnt/β-Catenin-Signale waren hauptsächlich im Zytoplasma, in den Nierentubuli und im Interstitium lokalisiert.

Schlussfolgerung

Urantid könnte AS-bedingte Leber- und Nierenschäden durch Antagonisierung des UII/UT-Systems verbessern; und die Verbesserungen der Leber- und Nierenfunktion arteriosklerotischen ApoE(−/−)-Mäusen könnten mit der Hemmung des Wnt/β-Catenin-Signalwegs zusammenhängen.

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Funding

This study received funding from the Hebei Provincial Natural Science Foundation (grant no. H2020406011), Hebei Provincial Party Committee Organization Department Youth Top Talent Project (grant no. JZZ [2016] No. 9), Hebei Provincial Science and Technology Department Science and Technology Innovation Guidance Special Project, Hebei Provincial Department of Education Key Project (grant no. ZD2019098), Hebei Provincial Department of Education Outstanding Youth Fund Project (grant no. YQ2013005), Chengde Medical College National Natural Science Foundation Project Cultivation Fund and Key Subjects (Pathology and Pathophysiology) at Colleges and Universities of Hebei Province(grant no. 201916), Natural Science Foundation for Youth of Chengde Medical College Cultivation Fund (KY202123),Basic Research Funds for Chengde Medical College in 2022 (KY202227).

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Authors and Affiliations

  1. Department of Pathophysiology, Chengde Medical University, Anyuan Road, 067000, Chengde, Hebei, China

    Yu-hang Xu, Jia-yi Xie, Shen Huang, Tu Wang, Hai-peng Cui &  Juan Zhao

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  1. Yu-hang Xu
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  2. Jia-yi Xie
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  3. Shen Huang
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  4. Tu Wang
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  5. Hai-peng Cui
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  6. Juan Zhao
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Contributions

JZ and YHX conceived and designed the study. YHX, JYX, SH, TW and HPC performed the experiments. HPC and TW were responsible for experimental technical guidance. SH analyzed the data. YHX wrote the paper. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Juan Zhao.

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Conflict of interest

This manuscript has been reviewed and approved for publication by Y.-h. Xu, J.-y. Xie, S. Huang, T. Wang, H.-p. Cui and J. Zhao without any conflicts of interest.

This study was approved by Chengde Medical University (Chengde, China). All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Xu, Yh., Xie, Jy., Huang, S. et al. Urantide alleviates atherosclerosis-related liver and kidney injury via the Wnt/β-catenin signaling pathway in ApoE(−/−) mice. Herz (2023). https://doi.org/10.1007/s00059-023-05219-w

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  • DOI: https://doi.org/10.1007/s00059-023-05219-w

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