Background: Vascular calcification (VC) is a major contributor to cardiovascular events and mortality in patients with chronic kidney disease (CKD). Tenascin C (TNC), a matricellular glycoprotein, has been implicated in fibrotic disorders, but its potential role in VC remains unexplored 

Methods: In vivo, CKD-associated VC was induced in rats and mice by 5/6 nephrectomy (5/6 Nx) combined with a high-phosphate diet. In vitro, primary VSMCs and aortic rings were cultured under high-phosphate conditions to induce osteogenic differentiation and calcification. Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (RNA-seq) were performed to profile gene expression landscape in calcified arteries. The functional role and underlying mechanism of TNC were investigated both TNC-knockout mice in vivo and in vitro experiments. Additionally, TCP7 peptides were tested for their protective effect against VC.

Results: Transcriptomic profiling revealed TNC as a candidate mediator of VSMCs osteogenic reprogramming. TNC expression was markedly upregulated in calcific arteries of CKD rats and in phosphate-induced osteogenic VSMCs. Genetic knockout of TNC significantly attenuated VC in vivo and in vitro, whereas the addition of recombinant human Tenascin C (rhTNC) protein exacerbated these effects in vitro. Mechanistically, TNC interacted with LRP6 and Wnt3a to activate β-catenin signaling, thereby promoting osteoblastic reprogramming of VSMCs. Notably, TCP7, a peptide derived from human TNC protein, competitively disrupted TNC/Wnt3a/LRP6 complex and effectively alleviated VC in vivo and in vitro.

Conclusions: These results suggest that TNC drives CKD-associated VC via recruiting and presenting Wnt ligands and facilitates β-catenin signaling. TCP7 could be a novel therapeutic remedy for halting the progression of VC.