Recombinant human soluble thrombomodulin is associated with attenuation of sepsis-induced renal impairment by inhibition of extracellular histone release

Multiple organ dysfunction induced by sepsis often involves kidney injury. Extracellular histones released in response to damage-associated molecular patterns are known to facilitate sepsis-induced organ dysfunction. Recombinant human soluble thrombomodulin (rhTM) and its lectin-like domain (D1) exert anti-inflammatory effects and neutralize damage-associated molecular patterns. However, the effects of rhTM and D1 on extracellular histone H3 levels and kidney injury remain poorly understood. Our purpose was to investigate the association between extracellular histone H3 levels and kidney injury, and to clarify the effects of rhTM and D1 on extracellular histone H3 levels, kidney injury, and survival in sepsis-induced rats. Rats in whom sepsis was induced via cecal ligation and puncture were used in this study. Histone H3 levels, histopathology of the kidneys, and the survival rate of rats at 24 h after cecal ligation and puncture were investigated. Histone H3 levels increased over time following cecal ligation and puncture. Histopathological analyses indicated that the distribution of degeneration foci among tubular epithelial cells of the kidney and levels of histone H3 increased simultaneously. Administration of rhTM and D1 significantly reduced histone H3 levels compared with that in the vehicle-treated group and improved kidney injury. The survival rates of rats in rhTM- and D1-treated groups were significantly higher than that in the vehicle-treated group. The results of this study indicated that rhTM and its D1 similarly reduce elevated histone H3 levels, thereby reducing acute kidney injury. Our findings also proposed that rhTM and D1 show potential as new treatment strategies for sepsis combined with acute kidney injury.