CKAP4 contributes to the progression of vascular calcification (VC) in chronic kidney disease (CKD) by modulating YAP...

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.