Sustained tenascin-C activation drives AKI-to-CKD progression via the Wnt/β-catenin pathway.

Acute kidney injury (AKI) serves as an independent risk factor contributing to the progression toward chronic kidney disease (CKD). Tenascin-C (TNC), an extracellular matrix glycoprotein, has been implicated in renal protection following AKI. However, its involvement in the transition from AKI to CKD remains unclear. This study investigates the role of TNC in murine models subjected to varying severities of ischemia/reperfusion injury (IRI), including mild IRI (20 min of ischemia) and severe IRI (30 min of ischemia). Mild IRI induced a transient renal dysfunction accompanied by transient TNC activation, followed by apparent recovery of renal structure and function within the period. In contrast, severe IRI triggered sustained and excessive TNC expression, coinciding with the onset of renal fibrosis. To assess the contribution of persistent TNC expression in promoting AKI-to-CKD progression, TNC was either overexpressed or silenced using shRNA plasmids. In vivo, TNC overexpression five days post-IRI activated β-catenin signaling and accelerated CKD development. Conversely, TNC knockdown suppressed β-catenin activation and mitigated disease progression. In vitro, TNC was found to interact with Wnt ligands via epidermal growth factor receptor (EGFR), as demonstrated by co-immunoprecipitation assays, thereby amplifying Wnt-induced β-catenin activation. These findings suggest that sustained, rather than transient, TNC activation may play a critical role in facilitating the AKI-to-CKD transition by modulating Wnt/β-catenin signaling through EGFR.