Tofogliflozin Delays Portal Hypertension and Hepatic Fibrosis by Inhibiting Sinusoidal Capillarization in Cirrhotic Rats

Background: Liver cirrhosis leads to portal hypertension (PH) with capillarization of liver sinusoidal endothelial cells (LSECs), although drug treatment options for PH are currently limited. Sodium glucose transporter 2 inhibitors, which are antidiabetic agents, have been shown to improve endothelial dysfunction. We aimed to elucidate the effect of tofogliflozin on PH and liver fibrosis in a rat cirrhosis model. Methods: Male-F344/NSlc rats repeatedly received carbon tetrachloride (CCl4) intraperitoneally to induce PH and liver cirrhosis alongside tofogliflozin (10 or 20 mg/kg). Portal hemodynamics and hepatic phenotypes were assessed after 14 weeks. An in vitro study investigated the effects of tofogliflozin on the crosstalk between LSEC and activated hepatic stellate cells (Ac-HSC), which are relevant to PH development. Results: Tofogliflozin prevented PH with attenuated intrahepatic vasoconstriction, sinusoidal capillarization, and remodeling independent of glycemic status in CCl4-treated rats. Hepatic macrophage infiltration, proinflammatory response, and fibrogenesis were suppressed by treatment with tofogliflozin. In vitro assays showed that tofogliflozin suppressed Ac-HSC-stimulated capillarization and vasoconstriction in LSECs by enhancing the antioxidant capacity, as well as inhibited the capilliarized LSEC-stimulated contractive, profibrogenic, and proliferative activities of Ac-HSCs. Conclusions: Our study provides strong support for tofogliflozin in the prevention of liver cirrhosis-related PH.