Yingxue Zhao, Yongjie Qin, Lanzhi He, Haikun Luo, Ying Mo, Weihai Zhou, Huamei He, Ganping Zhou, Xihua Liu
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.