tPA protects kidneys from Candida infection by suppressing RTEC apoptosis via LRP1/ERK1/2 signaling
Background
Invasive Candida albicans infections (candidiasis) are a major cause of morbidity and mortality, often leading to progressive organ damage, particularly in the kidneys. Fungal hyphal invasion directly induces apoptosis of renal tubular epithelial cells (RTEC), a critical driver of kidney pathology. Current antifungal therapies primarily target the pathogen, but host-directed strategies to protect renal tissue from damage remain largely undefined. Understanding intrinsic renal protective mechanisms is crucial for developing adjunctive therapies to mitigate tissue injury in severe infections.
Study Design
Researchers investigated the role of tissue-type plasminogen activator (tPA) in a mouse model of invasive candidiasis. They examined tPA induction in renal endothelial cells and RTEC, and its signaling pathways. To confirm the mechanism, they utilized mice with RTEC-specific deletion of LRP1 (low-density lipoprotein receptor-related protein 1). The study also involved administering a nonenzymatic form of tPA to infected mice to assess its protective effects on renal tubular epithelial cell apoptosis and overall kidney damage.
Results
Tissue-type plasminogen activator (tPA) was identified as a critical mediator of renal tissue protection in candidiasis. Its expression was induced by IL-17 and TNFα in renal endothelial cells and RTEC. Mechanistically, tPA signals through low-density lipoprotein receptor-related protein 1 (LRP1) and subsequently activates ERK1/2 signaling, which effectively suppresses apoptosis in RTEC. This protective axis was further confirmed by genetic manipulation: mice with RTEC-specific deletion of LRP1 exhibited significantly exaggerated kidney damage during candidiasis, highlighting LRP1's essential role in renal integrity. > Administration of a nonenzymatic form of tPA successfully recapitulated the protective effect of endogenous tPA, specifically by limiting RTEC apoptosis in infected mice. These findings collectively establish the tPA/LRP1 axis as a key intrinsic defense mechanism preserving renal integrity during invasive fungal infection.
Key Findings
- Tissue-type plasminogen activator (tPA) acts as a critical mediator of renal tissue protection in invasive candidiasis.
- tPA expression is induced by
IL-17andTNFαin renal endothelial cells and renal tubular epithelial cells (RTEC). - tPA signals through
LRP1and activatesERK1/2signaling to suppress apoptosis in RTEC. - Mice with
RTEC-specific deletion ofLRP1showed exaggerated kidney damage during candidiasis. - Administration of a nonenzymatic form of tPA limited
RTECapoptosis and protected against kidney damage.
Why It Matters
This research reveals a novel host-protective mechanism against invasive candidiasis and suggests a promising therapeutic strategy. Clinically approved tPA, traditionally used as a thrombolytic, could be repurposed as an adjunctive therapy to mitigate kidney damage in patients with severe fungal infections. This approach focuses on protecting host tissue rather than directly killing the pathogen, potentially reducing the reliance on antifungals and combating drug resistance. While preclinical, these findings lay the groundwork for future studies exploring tPA or its nonenzymatic variants as a host-directed intervention to preserve organ function in critical care settings, potentially improving outcomes for patients with candidiasis.
candidiasis
kidney-damage
tpa
lrp1
erk1/2
apoptosis