Recombinant human ADAMTS13 attenuates LPS-induced acute kidney injury and renal microangiopathy in murine advanced liver fibrosis by cleaving vWF.

Hepatorenal syndrome (HRS) has a poor prognosis among the complication of cirrhosis, yet treatment options are limited. Thrombotic microangiopathy with reduced ADAMTS13 activity and vWF accumulation has been reported to play a key role in the pathogenesis of acute kidney injury (AKI) in cirrhosis. This study investigated the effect of recombinant ADAMTS13 (rADAMTS13) on AKI with carbon tetrachloride (CCl4)-induced advanced liver fibrosis in mice. AKI was induced by intraperitoneal administration of acute insult with double dose of CCl4 and lipopolysaccharide (AKI-F mice), and mice were treated with rADAMTS13 (10 μg/body). AKI-F mice showed a marked liver dysfunction as well as renal dysfunction with elevated serum level of renal damage markers including kidney injury molecule-1, osteopontin, and neutrophil gelatinase-associated lipocalin. In AKI-F mice, reduced plasma ADAMTS13 activity and increased vWF antigen levels resulted in the decrease in hepatic and renal blood flow. Treatment with rADAMTS13 increased plasma ADAMTS13 activity, decreased vWF antigen levels leading to recovery of liver and kidney blood flow. Consequently, both hepatic and renal injuries showed serological and histopathologic improvements with decreased F4/80+ macrophage infiltration and 4-hydroxynonenal+ oxidative damage after rADAMTS13 treatment. The deposition of CD41a-positive microthrombi in kidney tissues observed in the AKI-F mice was significantly suppressed by treatment with rADAMTS13. Concomitantly, rADAMTS13 treatment promoted angiogenesis as well as inhibited vascular inflammation in the kidney of AKI-F mice. In conclusion, administration of rADAMTS13 may improve inflammation, oxidative stress, and reduced blood flow in liver and kidney tissues, thereby mitigating hepatorenal syndrome.