Cinacalcet ameliorates aortic calcification in uremic rats via suppression of endothelial-to-mesenchymal transition.
OBJECTIVE
Experimental studies found that cinacalcet (CINA) markedly attenuated vascular calcification in uremic rats, but its underlying mechanisms are still largely unknown. Recent evidence have demonstrated that endothelial cells (ECs) participate in ectopic calcification in part by mediating endothelial-to-mesenchymal transition (EndMT). In this study, we investigated whether CINA ameliorated aortic calcification in uremic rats via suppression of EndMT.


METHODS
Uremia was induced in rats by feeding rats a 0.75% adenine diet for 4 weeks. After adenine withdrawal, the rats were maintained on a 1.03% phosphorus diet for next 8 weeks. At initiation of the adenine diet, rats were orally administered CINA (10mg/kg one day) for 12 weeks. The aortic expression of EndMT- and chondrocyte- markers was examined. The effect of elevated PTH on EndMT was also studied in aortic ECs.


RESULTS
In uremic rats, CINA treatment significantly decreased the serum PTH concentrations, but did not affect the elevated levels of serum calcium (Ca), phosphorus (P) and Ca×P product. Besides, CINA significantly attenuated aortic calcification, and inhibited the expression of chondrocyte markers (SOX9 and COL2A1) and chondrocyte proteoglycan in uremic aortas. Moreover, CINA treatment largely abolished the up-regulation of mesenchymal markers (FSP1 and α-SMA) and down-regulation of the endothelial marker (CD31), which accompanied aortic calcification in uremic aorta samples. In vitro, PTH increased the expression of EndMT-markers in a concentration- and time-dependent manner.


CONCLUSIONS
These findings suggest that strategies aiming at reducing serum PTH might prevent uremic aortic calcification by abrogating EndMT.
Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China.
Min
M
Wu
Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China.
Ri-Ning
RN
Tang
Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China.
Hong
H
Liu
Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China.
Ming-Ming
MM
Pan
Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China.
Bi-Cheng
BC
Liu
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology; D057966:Calcimimetic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D008297:Male; D010281:Parathyroid Hormone / Q000097:blood; D017208:Rats, Wistar; D014511:Uremia / Q000150:complications / Q000473:pathology*; D061205:Vascular Calcification / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology
D057966:Calcimimetic Agents; D010281:Parathyroid Hormone