Yes-associated Protein Is Involved in Tubular Epithelial Cell Apoptosis and Renal Tissue Damage in Early Sepsis-Associated Acute Kidney Injury

Abstract

Abstract Sepsis-associated acute kidney injury (SA-AKI) is a distinct form of acute kidney injury in critically ill patients. It is characterized by tubular epithelial cell damage and apoptosis. The Hippo-Yes-associated protein (YAP) pathway plays dual roles in renal injury and repair, with YAP serving as a key downstream effector; however, its function during the early stages of SA-AKI remains unclear. In this study, we utilized two mouse models (lipopolysaccharide-induced and cecal ligation and perforation) and human proximal tubule epithelial cells (HK-2 cells) to investigate YAP’s roles in SA-AKI. YAP expression was manipulated by adeno-associated virus 9 (AAV9)-mediated overexpression and pharmacological inhibition with verteporfin. Renal injury markers, inflammatory cytokines, and related pathway proteins were evaluated. Histopathological analyses, including HE and PAS staining, revealed increased tubular cell apoptosis and tissue disruption. In both SA-AKI models, YAP expression and nuclear localization were significantly increased at 24 h after injury induction. YAP overexpression exacerbated renal injury and inflammatory responses, whereas pharmacological inhibition of YAP markedly attenuated kidney damage. Mechanistically, YAP-mediated renal injury was associated with dysregulation of the PI3K-AKT signaling pathway. In summary, these findings indicate that YAP may be involved in renal pathological damage in early SA-AKI and highlight its potential role in disease progression.