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Protective Roles of Xenotropic and Polytropic Retrovirus Receptor 1 (XPR1) in Uremic Vascular Calcification

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Abstract

Cellular phosphate transporters play critical roles in the pathogenesis of vascular calcification (VC) in chronic kidney disease (CKD). However, the mechanistic link between VC and xenotropic and polytropic receptor 1 (XPR1), a newly identified phosphate exporter, remains unknown. We developed a new mouse model with rapidly progressive uremic VC in C57BL/6 mice and examined the roles of XPR1. The combination of surgical heminephrectomy and 8 weeks of feeding a customized warfarin and adenine-based diet induced extensive aortic VC in almost all mice. The XPR1 mRNA level in the aorta of CKD mice was significantly lower than those in control mice as early as week 2, when there was no apparent VC, which progressively declined thereafter. Dietary phosphate restriction increased XPR1 mRNA expression in the aorta but reduced aortic VC in CKD mice. In cultured vascular smooth muscle cells (VSMCs), a calcifying medium supplemented with high phosphate and calcium did not affect XPR1 mRNA expression. The XPR1 mRNA expression in cultured VCMCs was also unaffected by administration of indoxyl sulfate or calcitriol deficiency but was decreased by 1–34 parathyroid hormone or fibroblast growth factor 23 supplementation. Furthermore, XPR1 deletion in the cultured VSMCs exacerbated calcification of the extracellular matrix as well as the osteogenic phenotypic switch under the condition of calcifying medium. Our data suggest that XPR1 plays protective roles in the pathogenesis of VC and its decrease in the aorta may contribute to the progression of VC in CKD.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code Availability

Software application or custom code used in this study is available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Mr. Mikio Munakata at the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University and Dr. Hirotaka Iura at the Department of Orthopaedic Surgery, Kyushu University for supporting the experiments. We thank the Research Support Center and Kyushu University Graduate School of Medical Sciences for technical support. We also thank Mitchell Arico from Edanz Group (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This study was supported by grants from the Japan Society for the Promotion of Science (Grant-in-Aid for Scientific Research 18H06224 and 19K08706) and the Kidney Foundation Japan [Grant for pathophysiological research conference in chronic kidney disease (JKFB 18-15)].

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Authors and Affiliations

  1. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi–Ku, Fukuoka, 8128582, Japan

    Hokuto Arase, Shunsuke Yamada, Toshiaki Nakano & Takanari Kitazono

  2. Department of Integrated Therapy for Chronic Kidney Disease, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 8128582, Japan

    Kumiko Torisu

  3. Department of Internal Medicine, Fukuoka Dental College, 2-15-1 Tamura, Sawara-Ku, Fukuoka, 8140193, Japan

    Masanori Tokumoto

  4. Fukuoka Renal Clinic, 4-6-20 Watanabe-Dori, Chuo-Ku, Fukuoka, 8100004, Japan

    Masatomo Taniguchi

  5. Department of Nephrology, Nara Medical University, 840 Shijo-Cho, Kashihara, Nara, 6348521, Japan

    Kazuhiko Tsuruya

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  1. Hokuto Arase
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Contributions

Research concept: HA, SY, and KTo; data analysis interpretation: HA, SY, KT, MTo, and MTa; supervision or mentorship: TN, KTs, and TK. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions that pertain to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. TN takes responsibility that this study has been reported honestly, accurately, and transparently, that no important aspects of the study have been omitted, and that any discrepancies from the study as planned have been explained.

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Correspondence to Toshiaki Nakano.

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Human and Animal Rights and Informed Consent

All animal procedures and protocols were approved by the Ethics Committee on Animal Experimentation, Kyushu University Graduate School of Medical Sciences (approval number A30-203). This article does not contain any studies with human subjects or human tissues performed by any of the authors.

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Arase, H., Yamada, S., Torisu, K. et al. Protective Roles of Xenotropic and Polytropic Retrovirus Receptor 1 (XPR1) in Uremic Vascular Calcification. Calcif Tissue Int 110, 685–697 (2022). https://doi.org/10.1007/s00223-022-00947-3

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