Department of Pharmacology, Faculty of Pharmacy, Gazi University, Etiler, 06330, Ankara, Turkey.
Department of Pathology, Faculty of Medicine, Ankara University, Sihhiye, 06100, Ankara, Turkey.
Mol Biol Rep. 2020 Mar;47(3):2243-2252. doi: 10.1007/s11033-020-05329-2. Epub 2020 Feb 19.
Hypertension is an important risk factor for cardiovascular diseases. Besides cardiovascular system, it could cause damage to liver. It has been shown that endoplasmic reticulum stress (ERS) plays a crucial role in the pathogenesis of hypertension. ERS inhibitor tauroursodeoxycholic-acid (TUDCA) has favorable effects on various pathologies including cardiovascular, metabolic and hepatic diseases. In this study, the hepatoprotective effect and mechanism of TUDCA were investigated in the deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Male Wistar rats were used and divided into four groups: Control, DOCA, TUDCA and DOCA + TUDCA. Hypertension was induced by DOCA-salt administration for twelve weeks after the unilateral nephrectomy. TUDCA was given for the last 4 weeks. Systolic blood pressure was measured by using tail-cuff method. At the end of the treatment, liver was isolated and weighed. The expressions of various proteins and histopathological evaluation were examined in the liver. TUDCA markedly decreased systolic blood pressure in the hypertensive animals. Hypertension caused increase in the expressions of glucose-regulated protein-78 (GRP78), matrix metalloproteinase-2 (MMP-2) and phospho-inhibitor κB-α (p-IκB-α) and the decrease in the expression of sarcoplasmic/endoplasmic reticulum Ca-ATPase2 (SERCA2) and phospho-extracellular signal-regulated kinase (p-ERK) in the liver. Alterations in these protein expressions were not detected in the TUDCA-treated hypertensive group. Also, hepatic balloon degeneration, inflammation and fibrosis were observed in the hypertensive group. TUDCA improved inflammation and fibrosis in the hypertensive liver. Our findings indicate that the detrimental effect of DOCA-salt-induced hypertension on the liver was defended by the inhibition of ERS. Hepatic ERS and its treatment should be taken into consideration for therapeutic approaches to hypertension.
高血压是心血管疾病的重要危险因素。除了心血管系统，它还可能对肝脏造成损害。已经表明，内质网应激（ERS）在高血压的发病机制中起着关键作用。内质网应激抑制剂牛磺熊脱氧胆酸（TUDCA）对心血管、代谢和肝脏疾病等多种疾病都有良好的治疗作用。在这项研究中，我们研究了 TUDCA 在去氧皮质酮醋酸盐（DOCA）-盐诱导的高血压中的保肝作用及其机制。雄性 Wistar 大鼠被分为四组：对照组、DOCA 组、TUDCA 组和 DOCA+TUDCA 组。单侧肾切除后，用 DOCA-盐进行十二周诱导高血压，最后四周给予 TUDCA。用尾套法测量收缩压。治疗结束时，分离肝脏并称重。检测肝脏中各种蛋白质的表达和组织病理学评价。TUDCA 显著降低了高血压动物的收缩压。高血压导致葡萄糖调节蛋白 78（GRP78）、基质金属蛋白酶 2（MMP-2）和磷酸化抑制κB-α（p-IκB-α）的表达增加，而肌浆/内质网 Ca-ATPase2（SERCA2）和磷酸化细胞外信号调节激酶（p-ERK）的表达减少。在 TUDCA 治疗的高血压组中未检测到这些蛋白质表达的改变。此外，高血压组还观察到肝气球样变性、炎症和纤维化。TUDCA 改善了高血压肝脏的炎症和纤维化。我们的研究结果表明，DOCA-盐诱导的高血压对肝脏的有害影响通过抑制内质网应激得到了防御。肝脏 ERS 及其治疗应被考虑用于高血压的治疗方法。
