Department of Gastroenterology, Nara Medical University, Kashihara 634-8521, Nara, Japan.
Cells. 2024 Mar 19;13(6):538. 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.
肝硬化导致门静脉高压（PH），伴有肝窦内皮细胞（LSEC）的毛细血管化，尽管目前 PH 的药物治疗选择有限。钠-葡萄糖共转运蛋白 2 抑制剂是一种抗糖尿病药物，已被证明可改善内皮功能障碍。我们旨在阐明托格列净对 CCl 诱导的大鼠肝硬化模型中 PH 和肝纤维化的影响。
雄性 F344/NSlc 大鼠反复腹腔内接受四氯化碳（CCl）以诱导 PH 和肝硬化，同时给予托格列净（10 或 20mg/kg）。14 周后评估门脉血液动力学和肝表型。体外研究探讨了托格列净对 LSEC 与活化的肝星状细胞（Ac-HSC）之间相互作用的影响，这与 PH 的发展有关。
托格列净预防了 PH，减轻了 CCl 处理大鼠的肝内血管收缩、窦状毛细血管化和重塑，而与血糖状态无关。肝巨噬细胞浸润、促炎反应和纤维化均被托格列净治疗所抑制。体外实验表明，托格列净通过增强抗氧化能力抑制了 Ac-HSC 刺激的 LSEC 毛细血管化和血管收缩，并抑制了毛细血管化的 LSEC 刺激的 Ac-HSC 的收缩、促纤维化和增殖活性。
我们的研究为托格列净预防肝硬化相关 PH 提供了有力支持。
