CKAP4 contributes to the progression of vascular calcification (VC) in chronic kidney disease (CKD) by modulating YAP phosphorylation and MMP2 expression
CKAP4 contributes to the progression of vascular calcification (VC) in chronic kidney disease (CKD) by modulating YAP phosphorylation and MMP2 expression
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DOI：
10.1016/j.cellsig.2022.110270
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发表时间：
2022-03-08
影响因子：
4.8
通讯作者：
Rong, Shu
中科院分区：
文献类型：
--
作者：
Shi, Yuping;Jin, Xiucai;Rong, Shu
慢性肾脏疾病(CKD)是一个与高死亡率相关的日益严重的公共卫生问题。血管钙化(VC)的发生与CKD的进展相一致。在CKD中，高磷血症促进中间VC，这一过程由血管平滑肌细胞(VSMCs)启动成骨转分化而进一步促进。本研究的目的是确定CKAP4在VC进展中的作用。临床研究表明，CKAP4和基质金属肽酶2(MMP2)水平升高与CKD的发病密切相关。作为一种体外模型，提取小鼠血管平滑肌细胞，并用高水平的磷酸盐(2.5mmo1/L Pi)处理。我们还建立了由5/6肾切除和高蛋白饮食(高PI饮食)诱导的CKD小鼠体内模型。CKAP4和MMP2在体外和体内模型中的表达在两种模型的VSMCs和钙化的主动脉中均显著升高。此外，体外实验表明，CKAP4调节YAP的磷酸化。同时沉默CKAP4和钙含量测定显示，主动脉VSMC和钙含量显著降低。茜素红染色和钙含量测定显示，沉默CKAP4可减少VSMC和主动脉钙化，并减少YAP和MMP2的表达。总之，我们的研究首次证明了CKAP4通过调节YAP的磷酸化和MMP2的表达在CKD的VC中起作用。
Chronic kidney disease (CKD) is an growing public health concern associated with high mortality rates. The occurrences of vascular calcification (VC) increase concordantly with the progression of CKD.With CKD, hyperphosphatemia promotes intermediate VC, a process that is further facilitated by vascular smooth muscle cells (VSMCs) initiating osteogenic transdifferentiation. The purpose of this study was to determine the involvement of CKAP4 in VC progression. Clinical investigations demonstrate that elevated blood CKAP4 and matrix metallopeptidase 2 (MMP2) levels are related with CKD in individuals. As an in vitro model, mouse VSMCs were extracted and treated with high levels of phosphates (2.5 mmol/L Pi). We also created an in vivo mice model of CKD induced by 5/6 nephrophrectomies and a high-protein diet (High Pi diet). The expression of CKAP4 and MMP2 in both in vitro and in vivo models was significantly higher in VSMCs and calcified aorta in both models. Additionally, in vitro tests indicated that CKAP4 modulates YAP phosphorylation. Simultaneous silencing of CKAP4 and calcium content assay revealed a significant reduction in the VSMCs and calcium content of the aorta. Alizarin red staining and calcium content assay reveled that silencing of CKAP4 reduced the VSMCs and aortic calcification, accompanied with reduced expression of YAP and MMP2. Overall, our study demonstrates for the first time that CKAP4 contributes to VC in CKD by modulating YAP phosphorylation and MMP2 expression.