대한신장학회

논문분류	춘계학술대회 초록집
제목	Toll-like receptor 4 mediates histone-induced endothelial dysfunction in septic acute kidney injury.
저자	Yang Tinghang
출판정보	2024; 2024(1):
키워드
초록	Objectives: With the increasing understanding of the roles of circulating histones and endothelial dysfunction in sepsis, we investigated the mechanism of histone-induced endothelial dysfunction leading to acute kidney injury in sepsis, and explored the potential therapeutic targets of Septic-AKI. Methods: Human umbilical vein endothelial cells (HUVEC) were exposed to purified human recombinant histone H3 with or without the selective Toll-4 inhibitor, TAK-242, and cell viability was determined by flow cytometry and cell counting kit-8. Immunofluorescence staining and western blot technology were used to investigate the expression of VE-cadherin qualitatively and quantitatively. Similarly, we constructed septic murine models by cecal ligation and puncture with or without TAK-242 administration. After 24 hours, the concentrations of serum creatinine, urea nitrogen, IL-6, IL-1β, and TNF-α were detected. Western blot technology was performed to detect the expression of renal endothelial adherens and neutrophil Gelatinase-associated Lipocalin (NGAL). Hematoxylin-eosin staining observed the pathological changes in kidney tissue. Endothelial permeability was represented by the Evans Blue captured per milligram of tissue that was intravenously injected 30 minutes before sacrifice. Results: Histone-induced endothelial cell apoptosis and endothelial barrier disruption in a dose-dependent manner. Usage of TAK-242 significantly ameliorated histone-induced decreased expression of VE-Cadherin and stabilized the integrity of the endothelial barrier. Consistently, TAK-242 significantly alleviated the increase of creatinine, urea nitrogen, and IL-6 induced by sepsis. Meanwhile, the down-regulation of renal VE-Cadherin, the increasing permeability of the renal endothelial barrier, and the pathological damage of renal tissue in mice were significantly improved. Interestingly, we found that blocking the TLR-4 receptor alone significantly induced the high expression of VE-Cadherin and stabilized the function of the renal endothelial barrier both in vivo and in vitro study. Conclusions: Our results demonstrate that TLR4 signaling is involved in histone-induced endothelial barrier disruption. Blocking the binding of histones to TLR-4 has a protective effect on septic renal injury.
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