Kidney Week

Abstract: SA-OR103

Cinacalcet Ameliorates Cardiac Valve Calcification in CKD via Suppressing Endothelial-to-Osteoblast Transition

Session Information

• Vascular Calcification, FGF-23, and Phosphate
  October 27, 2018 | Location: 33C, San Diego Convention Center
  Abstract Time: 05:30 PM - 05:42 PM

Category: Bone and Mineral Metabolism

• 401 Bone and Mineral Metabolism: Basic

Authors

• Wang, Li-ting, Institute of Nephrology, ZhongDa Hospital, school of medicine, Southeast University, Nanjing, China

Li-ting Wang, PhD

• Song, Kai-yun, Institute of Nephrology, ZhongDa Hospital, school of medicine, Southeast University, Nanjing, China

Kai-yun Song,

• Ni, Li-Hua, Institute of Nephrology, ZhongDa Hospital, school of medicine, Southeast University, Nanjing, China

Li-Hua Ni,

• Wang, Xiao-chen, Institute of Nephrology, ZhongDa Hospital, school of medicine, Southeast University, Nanjing, China

Xiao-chen Wang,

• Zuo, Meng, Institute of Nephrology, ZhongDa Hospital, school of medicine, Southeast University, Nanjing, China

Meng Zuo,

• Zhang, Yu-xia, Institute of Nephrology, ZhongDa Hospital, school of medicine, Southeast University, Nanjing, China

Yu-xia Zhang,

• Liu, Bi-Cheng, Institute of Nephrology, ZhongDa Hospital, school of medicine, Southeast University, Nanjing, China

Bi-Cheng Liu,

• Tang, Ri-ning, Institute of Nephrology, ZhongDa Hospital, school of medicine, Southeast University, Nanjing, China

Ri-ning Tang,

Background

Clinical studies found cinacalcet (CINA) markedly ameliorated cardiac valve calcification in chronic kidney disease (CKD) patients, but it underlying mechanisms are still unknown. Previous studies demonstrated endothelial cell participate in ectopic calcification in part by mediating endothelial-to-mesenchymal transition (EndMT) that could be transitioned into mesenchymal stem cells and further differentiated into osteoblast. Thus we investigated whether cinacalcet ameliorated cardiac valve calcification in two CKD models via suppression of endothelial-to-osteoblast transition.

Methods

SD rats were randomly divided into three group: control group (CTL, n=10), CKD group(n=30), and CINA treatment group(n=30). CKD group were established by 5/6 nephrectomy (n=15) or 0.75% adenine (n=15) for 4 weeks, both followed with 2.0% phosphorus diet for next 8 weeks. Meanwhile, rats of CINA treatment group were orally administered CINA (10 mg/kg one day). The expression of EndMT and osteoblast markers in valve was examined with the use of western blot, real time PCR, immunofluorescence staining and immunohistochemistry. Pathological examinations of the valves included histological characterization and Von Kossa staining. And we finished echocardiography for three groups. Besides, the important makers of Notch signal pathway were also detected in our study with the use of western blot and real time PCR.

Results

In CKD rats, CINA treatment significantly decreased the serum PTH concentration, calcium but did not affect the elevated levels of serum creatinine, blood urea nitrogen and phosphorus. Besides, CINA significantly attenuated aortic valve calcification, and inhibited the expression of osteogenic markers (osteopontin and osterix). Moreover, CINA treatment largely abolished the up-regulation of mesenchymal markers (FSP1 and α-SMA)， stem cell markers (CD44 and CD10) and down-regulation of the endothelial marker (CD31, E-cadherin), which accompanied calcification in CKD aortic valve samples. Besides, Notch signal pathway was activated with Notch1, NICD, HES and HEY increased, while CINA could ameliorates this process.

Conclusion

These findings suggest CINA could attenuate valve calcification by abrogating Notch mediated endothelial-to-osteoblast transition in rats with CKD.