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

• Published in: Cells (Basel, Switzerland) Vol. 13; no. 6; p. 538
• Main Authors: Asada, Shohei, Kaji, Kosuke, Nishimura, Norihisa, Koizumi, Aritoshi, Matsuda, Takuya, Tanaka, Misako, Yorioka, Nobuyuki, Sato, Shinya, Kitagawa, Koh, Namisaki, Tadashi, Akahane, Takemi, Yoshiji, Hitoshi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2024; MDPI
• Subjects: angiogenesis; Animals; Ascites; Benzhydryl Compounds; Carbon tetrachloride; Care and treatment; Cirrhosis; Complications and side effects; Cystic fibrosis; Diabetes mellitus; Dosage and administration; Endothelial cells; Endothelial Cells - pathology; Fibrosis; Glucose; Glucose transporter; Glucosides; Growth factors; Hemodynamics; hepatic stellate cell; Hepatocytes; Hypertension; Hypertension, Portal - drug therapy; Hypoglycemic agents; Inflammation; Laboratory animals; Liver; Liver cirrhosis; Liver Cirrhosis - pathology; Liver diseases; liver sinusoidal endothelial cell; Macrophages; Male; Nitric oxide; oxidative stress; Phenotypes; Portal hypertension; Prevention; Rats; Rats, Inbred F344; Risk factors; Science; sodium glucose transporter 2 inhibitors; Stellate cells; Vasoconstriction; Veins & arteries; Japan; United States > US; liver sinusoidal endothelial cell; hepatic stellate cell; sodium glucose transporter 2 inhibitors; angiogenesis; oxidative stress
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells13060538

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. Male-F344/NSlc rats repeatedly received carbon tetrachloride (CCl ) 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. Tofogliflozin prevented PH with attenuated intrahepatic vasoconstriction, sinusoidal capillarization, and remodeling independent of glycemic status in CCl -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. Our study provides strong support for tofogliflozin in the prevention of liver cirrhosis-related PH.