Cinacalcet ameliorates aortic calcification in uremic rats via suppression of endothelial-to-mesenchymal transition  

作　　者：Min WU Ri-ning TANG Hong LIU Ming-ming PAN Bi-cheng LIU 

机构地区：[1]Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing 210009, China

出　　处：《Acta Pharmacologica Sinica》2016年第11期1423-1431,共9页中国药理学报（英文版）

基　　金：These studies were supported by grants from the National Natural Science Foundation of China （81130010, 81470997, 31571186, and 81500545）, Natural Science Foundation of Jiangsu Province （BK20150640） and Clinic Research Center of Jiangsu Province （BL2014080）.

摘　　要：Aim： Experimental studies found that cinacalcet （ClNA） 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 ClNA 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 ClNA （10 mg/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, ClNA treatment significantly decreased the serum PTH concentrations, but did not affect the elevated levels of serum calcium （Ca）, phosphorus （P） and CaxP product. Besides, ClNA significantly attenuated aortic calcification, and inhibited the expression of chondrocyte markers （SOX9 and COL2A1） and chondrocyte proteoglycan in uremic aortas. Moreover, ClNA 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. Conclusion： These findings suggest that strategies aiming at reducing serum PTH might prevent uremic aortic calcification by abrogating EndMT.Aim： Experimental studies found that cinacalcet （ClNA） 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 ClNA 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 ClNA （10 mg/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, ClNA treatment significantly decreased the serum PTH concentrations, but did not affect the elevated levels of serum calcium （Ca）, phosphorus （P） and CaxP product. Besides, ClNA significantly attenuated aortic calcification, and inhibited the expression of chondrocyte markers （SOX9 and COL2A1） and chondrocyte proteoglycan in uremic aortas. Moreover, ClNA 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. Conclusion： These findings suggest that strategies aiming at reducing serum PTH might prevent uremic aortic calcification by abrogating EndMT.

关 键 词：CINACALCET UREMIA aortic calcification endothelial cells parathyroid hormone endothelial-to-mesenchymal transition 

分 类 号：R[医药卫生]