Portal hypertension contributes to ascites formation via the Piezo1-nuclear factor kappa-B-aquaporin1 pathway in liver cirrhosis.

Portal hypertension is critical to the development of ascites in liver cirrhosis. The aim of our study was to evaluate the contribution of portal hypertension to ascites formation and explore the underlying mechanism. Here, the role of portal hypertension in cirrhotic ascites was determined through a meta-analysis of portal pressure in cirrhotic patients and animal models. The mechanism underlying the involvement of portal hypertension in ascites formation was explored. The meta-analysis showed hepatic venous pressure gradient in patients with cirrhosis with ascites was significantly higher than that in patients with cirrhosis without ascites. In carbon tetrachloride (CCl)-treated rats, portal pressure of cirrhotic rats with ascites (19.83 cmHO) was significantly higher than that in cirrhotic rats without ascites (14.90 cmHO). In a novel murine model created by thioacetamide (TAA)/CCl administration plus partial portal vein ligation (PPVL), a significant increase in portal pressure and ascites amount was observed in the TAA/CCl + PPVL group compared with the TAA/CCl group. In the mice treated with TAA/CCl plus PPVL, the amount of ascites decreased significantly in mice with endothelial deletion of Piezo1 (Piezo1) compared with Piezo1 mice. Finally, Piezo1 in liver sinusoidal endothelial cells and peritoneal endothelial cells promoted the development of portal hypertensive ascites via the nuclear factor kappa-B (NF-ĸB)-aquaporin1 (AQP1) pathway. In conclusion, Piezo1 in endothelium contributes to the formation of portal hypertensive ascites via the NF-ĸB-AQP1 pathway in liver cirrhosis, which indicates that blockage of the Piezo1-NFĸB-AQP1 pathway may be a useful strategy for the management of ascites in liver cirrhosis.