Chang Jin Rui, Guo Jun, Wang Yue, Hou Yue Long, Lu Wei Wei, Zhang Jin Sheng, Yu Yan Rong, Xu Ming Jiang, Liu Xiu Ying, Wang Xiu Jie, Guan You Fei, Zhu Yi, Du Jie, Tang Chao Shu, Qi Yong Fen
The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, China; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated with the Capital Medical University, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China; Insititute of Basic Medicine Science, Xi'an Medical University, Xi'an, China.
The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, China; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated with the Capital Medical University, Beijing, China.
Kidney Int. 2016 Mar;89(3):586-600. doi: 10.1016/j.kint.2015.12.029. Epub 2016 Jan 28.
Deficiency in α-Klotho is involved in the pathogenesis of vascular calcification. Since intermedin (IMD)1-53 (a calcitonin/calcitonin gene-related peptide) protects against vascular calcification, we studied whether IMD1-53 inhibits vascular calcification by upregulating α-Klotho. A rat model of chronic kidney disease (CKD) with vascular calcification induced by the 5/6 nephrectomy plus vitamin D3 was used for study. The aortas of rats with CKD showed reduced IMD content but an increase of its receptor, calcitonin receptor-like receptor, and its receptor modifier, receptor activity-modifying protein 3. IMD1-53 treatment reduced vascular calcification. The expression of α-Klotho was greatly decreased in the aortas of rats with CKD but increased in the aortas of IMD1-53-treated rats with CKD. In vitro, IMD1-53 increased α-Klotho protein level in calcified vascular smooth muscle cells. α-Klotho knockdown blocked the inhibitory effect of IMD1-53 on vascular smooth muscle cell calcification and their transformation into osteoblast-like cells. The effect of IMD1-53 to upregulate α-Klotho and inhibit vascular smooth muscle cell calcification was abolished by knockdown of its receptor or its modifier protein, or treatment with the protein kinase A inhibitor H89. Thus, IMD1-53 may attenuate vascular calcification by upregulating α-Klotho via the calcitonin receptor/modifying protein complex and protein kinase A signaling.
α-klotho缺乏参与血管钙化的发病机制。由于中间介质（IMD）1-53（一种降钙素/降钙素基因相关肽）可预防血管钙化，我们研究了IMD1-53是否通过上调α-klotho来抑制血管钙化。采用5/6肾切除加维生素D3诱导的慢性肾脏病（CKD）伴血管钙化大鼠模型进行研究。CKD大鼠的主动脉显示IMD含量降低，但其受体降钙素受体样受体及其受体修饰因子受体活性修饰蛋白3增加。IMD1-53治疗可减少血管钙化。α-klotho的表达在CKD大鼠的主动脉中显著降低，但在接受IMD1-53治疗的CKD大鼠的主动脉中增加。在体外，IMD1-53增加了钙化血管平滑肌细胞中α-klotho蛋白水平。敲低α-klotho可阻断IMD1-53对血管平滑肌细胞钙化及其向成骨样细胞转化的抑制作用。敲低其受体或其修饰蛋白，或用蛋白激酶A抑制剂H89处理，可消除IMD1-53上调α-klotho和抑制血管平滑肌细胞钙化的作用。因此，IMD1-53可能通过降钙素受体/修饰蛋白复合物和蛋白激酶A信号通路上调α-klotho来减轻血管钙化。
