TNFα and endothelial IL-1 receptor signaling drive peritubular capillary regression and mature collagen accumulation...

Capillary regression destabilizes tissue homeostasis and contributes to chronic organ dysfunction, yet the inflammatory pathways that drive pathological vessel loss remain incompletely defined. We previously identified the inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin-1 (IL-1) as conserved mediators of physiological vessel regression in the neonatal mouse eye, but whether these cytokines contribute to pathological capillary regression in adult mice is unknown. In this study, we investigated the capillary regression that occurs along with inflammation in murine kidneys following irreversible unilateral ureteral obstruction (UUO) surgical challenge. Mice lacking genes encoding global TNFα, the endothelial IL-1 receptor IL-1R1, or both (double knockout, DKO) were examined at 10 days after UUO surgery. Although loss of the individual genes did not affect peritubular capillary (PTC) regression, PTC regression was significantly reduced in DKO mice. This reduction in PTC regression correlated with less expression of the proximal tubular epithelial injury marker KIM-1. DKO kidneys also displayed less accumulation of mature collagen fibers by Picrosirius Red and Masson's trichrome staining. These findings demonstrate that TNFα and endothelial IL-1R1 cooperatively drive pathological capillary regression in the irreversible UUO model of chronic kidney injury and that preservation of PTCs correlates with less proximal renal tubular injury and lower levels of mature collagen at 10 days after injury.NEW & NOTEWORTHY Pathological PTC regression drives progressive kidney injury, but its inflammatory triggers are unclear. Using the UUO model, we identified cooperative TNFα and endothelial IL-1R1 signaling as key drivers of capillary loss. Although deletion of either pathway alone was insufficient, combined loss preserved PTCs and reduced both proximal tubular injury and mature collagen accumulation. These findings highlight synergistic inflammatory signaling in microvascular loss and suggest that dual targeting may help preserve PTC integrity in chronic kidney disease.