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Uremic toxin indoxyl sulfate induces dysfunction of vascular smooth muscle cells via integrin-β1/ERK signaling pathway

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Abstract

Background

Protein-bound uremic toxins (PBUTs) are reported to be one of the major culprits in chronic kidney disease–cardiovascular disease (CKD–CVD) development, yet its mechanism is not fully clear. Our previous study confirmed elevated expression of integrin-β1 (ITGβ1) in vascular smooth muscle cells of uremic patients. Thus, this study aimed to explore the relationship between PBUTs and ITGβ1 in uremic vasculature injury.

Methods

Human umbilical vein smooth muscle cells (HUVSMCs) and endothelial cells (HUVECs) were treated with two representative PUBTs, indoxyl sulfate (IS) and p-cresyl sulfate (PC). Both cells were measured for the expression of ITGβ1 and downstream signaling pathways and assayed for proliferation, migration, adhesion and apoptosis.

Results

The IS treatments were observed with significantly up-regulated ITGβ1 in HUVSMCs but not in HUVECs, while PC did not induce ITGβ1 alteration in either HUVSMCs or HUVECs. Furthermore, overexpression of ITGβ1 revealed activated downstream signal-regulated kinase (ERK) signaling pathway with promoted focal adhesion, migration, proliferation but no apoptosis in HUVSMCs by IS. These functional and pathway alterations could be significantly suppressed by RNA interference of ITGβ1. More importantly, the application of ERK1/2 inhibitor significantly suppressed the focal adhesion, migration and proliferation of HUVSMCs.

Conclusion

We first demonstrated that ITGβ1/ERK signaling pathway mediated abnormal focal adhesion, migration and proliferation of vascular smooth muscle cells stimulated by IS. ITGβ1/ERK signaling may serve as a novel therapeutic target for CKD-CVD.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (#81971822).

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Authors and Affiliations

  1. Division of Nephrology, Center for Nephrology and Clinical Metabolomics, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China

    Haibo Yu, Chunyu Zhou, Dayong Hu, Changbin Li, Wen Xue & Ai Peng

  2. Department of Nephrology, Qilu Hospital of Shandong University (Qingdao), Qingdao, People’s Republic of China

    Qiang Wang

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  1. Haibo Yu
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  2. Chunyu Zhou
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  3. Dayong Hu
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  4. Changbin Li
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  7. Ai Peng
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Correspondence to Wen Xue or Ai Peng.

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10157_2022_2195_MOESM1_ESM.docx

Fig. S1 mRNA expression of ITGβ1 with gene knockdown by si-ITGβ1. Data are presented as the mean ± standard deviation of three independent experiments. **P < 0.01compared with NC group with Student’s t test. NC negative control, si-ITGβ1 ITGβ1-siRNA

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Yu, H., Zhou, C., Hu, D. et al. Uremic toxin indoxyl sulfate induces dysfunction of vascular smooth muscle cells via integrin-β1/ERK signaling pathway. Clin Exp Nephrol 26, 640–648 (2022). https://doi.org/10.1007/s10157-022-02195-z

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  • DOI: https://doi.org/10.1007/s10157-022-02195-z

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