Inositol 1,4,5-trisphosphate receptor type 2 is associated with the bone–vessel axis in chronic kidney disease–mineral bone disorder

Abstract

Objective

The pathogenesis of renal osteopathy and cardiovascular disease suggests the disordered bone–vessel axis in chronic kidney disease–mineral bone disorder (CKD–MBD). However, the mechanism of the bone–vessel axis in CKD–MBD remains unclear.

Methods

We established a CKD–MBD rat model to observe the pathophysiological phenotype of the bone–vessel axis and performed RNA sequencing of aortas to identify novel targets of the bone–vessel axis in CKD–MBD.

Results

The microarchitecture of the femoral trabecular bone deteriorated and alveolar bone loss was aggravated in CKD–MBD rats. The intact parathyroid hormone and alkaline phosphatase levels increased, 1,25-dihydroxyvitamin D3 levels decreased, and intact fibroblast growth factor-23 levels did not increase in CKD–MBD rats at 16 weeks; other bone metabolic parameters in the serum demonstrated dynamic characteristics. With calcium deposition in the abdominal aortas of CKD–MBD rats, RNA sequencing of the aortas revealed a significant decrease in inositol 1,4,5-trisphosphate receptor type 2 (ITPR2) gene levels in CKD–MBD rats. A similar trend was observed in rat aortic smooth muscle cells. As a secretory protein, ITPR2 serum levels decreased at 4 weeks and slightly increased without statistical differences at 16 weeks in CKD–MBD rats. ITPR2 serum levels were significantly increased in patients with vascular calcification, negatively correlated with blood urea nitrogen levels, and positively correlated with serum tartrate-resistant acid phosphatase 5b levels.

Conclusion

These findings provide preliminary insights into the role of ITPR2 in the bone–vessel axis in CKD–MBD. Thus, ITPR2 may be a potential target of the bone–vessel axis in CKD–MBD.

Keywords:

• Bone–vessel axis
• chronic kidney disease–mineral bone disorder
• clinical relevance
• inositol 1,4,5-trisphosphate receptor type 2
• vascular calcification

Acknowledgments

This study was supported in part by the University of Electronic Science and Technology, Sichuan Academy of Medical Sciences, and the Sichuan Provincial People’s Hospital. The authors thank Profs. Zhenglin Yang and Shaoping Deng of the Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital for generously providing the research platforms and technical support. The authors are indebted to Prof. Pengfei Zhou at the Stomatological Hospital of Chongqing Medical University for the ongoing support. We thank Dr. Shisheng Wang at the West China Hospital of Sichuan University for providing advice on data analysis.

Ethical approval

All the experiments were approved by the Institutional Review Board of the Animal Experiments Center of the Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital (No. 2017. 36).

Author contributions

QX, LW, GL, and YL collaborated with study design. QX, YT, HL, SC, RC, QT, and LX collected data. DH contributed to clinical data analysis. QX wrote the manuscript. QX, JX, DH, GL, and YL contributed to final revision of the manuscript.

Disclosure statement

An early version of this article was uploaded to a noncommercial preprint server. The following URL is linked to the preprint page: http://ssrn.com/abstract=4155291.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [U21A20349, 82270729, 81700607, 8170742, 82070690, 81970641 and 81800613]; the PHD Foundation of Sichuan Academy of Sciences & Sichuan Provincial People’s Hospital [2015BS05]; the Fundamental Research Funds for the Central Universities from UESTC [ZYGX2019J105]; Key R & D projects in Sichuan Province [2019YFS0538 and 2021YFS0370]; the Department of Science and Technology of Sichuan Province [2020ZYD034 and 2021YFS0372]; the Foundation of Health and Family Planning Commission in Sichuan [16PJ424]; the Foundation of Sichuan Medical Association [S20071]; the Zhongguancun Nephrology & Blood Purification Innovation Alliance [NBPIA20QC0102] and the Discipline Construction Fund of Sichuan Provincial People’s Hospital.