Hirudin Attenuates Uric Acid-Induced Renal Tubular Injury via TNFRSF6B-Mediated Suppression of NF-κB Signaling.

Hyperuricemia, characterized by elevated serum uric acid (SUA) levels, is increasingly recognized as a pathological contributor to renal injury through oxidative stress, inflammation, and apoptosis. Hirudin, a thrombin inhibitor derived from leech saliva, has recently been noted for its anti-inflammatory properties, yet its role in hyperuricemia remains unclear. This study aimed to investigate the protective effects and underlying mechanisms of hirudin in a uric acid (UA)-induced renal tubular epithelial injury model. Using HK-2 cells, we found that hirudin enhanced cell viability and reduced apoptosis in UA-treated conditions. Mechanistically, these protective effects were mediated through downregulation of TNFRSF6B, a decoy receptor involved in inflammatory and apoptotic signaling. TNFRSF6B knockdown potentiated hirudin's cytoprotective effects, whereas its overexpression reversed them. Hirudin treatment attenuated UA-induced expression of urate transporters (URAT1, GLUT9, and OAT4) and pro-inflammatory cytokine IL-1β, both at the transcriptional and protein levels. Moreover, hirudin suppressed activation of the NF-κB signaling pathway, a critical mediator of inflammation and apoptosis in hyperuricemia, with transcriptomic and immunoblotting data confirming downregulation of NF-κB-associated targets. Co-treatment with JSH-23, an NF-κB inhibitor, further reinforced these findings and highlighted a TNFRSF6B/NF-κB axis as a key regulatory mechanism. Collectively, these findings reveal a novel protective role for hirudin in UA-induced renal injury, mediated via modulation of TNFRSF6B and suppression of NF-κB signaling. This study provides new insight into the potential therapeutic application of hirudin in hyperuricemia-associated kidney damage.