Tissue-type plasminogen activator protects against kidney damage in invasive fungal infection.

Invasive Candida albicans infections (candidiasis) cause progressive organ damage through fungal tissue invasion and toxin-mediated injury, including in the kidney. Hyphal invasion induces apoptosis of renal tubular epithelial cells (RTEC), a key driver of kidney pathology, yet intrinsic renal protective mechanisms remain poorly defined. We identify fibrinolytic tissue-type plasminogen activator (tPA) as a critical mediator of renal tissue protection in candidiasis. tPA is induced by IL-17 and TNFα in renal endothelial cells and RTEC. tPA signals through low-density lipoprotein receptor-related protein 1 (LRP1) and activates ERK1/2 signaling to suppress apoptosis in RTEC. Mice with RTEC-specific deletion of LRP1 exhibited exaggerated kidney damage during candidiasis. Administration of a nonenzymatic form of tPA recapitulated the protective effect of tPA by limiting RTEC apoptosis. These findings reveal the role of tPA/LRP1 axis in preserving renal integrity in candidiasis and suggest clinically approved tPA as a potential therapeutic strategy to mitigate candidiasis-associated tissue injury.