Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.
Faculty of medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Clin Sci (Lond). 2020 Aug 14;134(15):2055-2073. doi: 10.1042/CS20200452.
BACKGROUNDS/AIMS: The present study explores the potential of chronic treatment with the Foresaid X receptor (FXR) agonist obeticholic acid (OCA), which inhibits oxidative stress-related pathogenesis, in ascitic cirrhotic rats with hepatorenal syndrome (HRS) developed 6 weeks after bile duct ligation (BDL).
Systemic, splanchnic, and renal hemodynamics and pathogenic cascades were measured in ascitic BDL and sham rats receiving 2-weeks of either vehicle or OCA treatments (sham-OCA and BDL-OCA groups), and NRK-52E cells, rat kidney tubular epithelial cells.
Chronic OCA treatment significantly normalized portal hypertension, glomerular filtration rate, urine output, renal blood flow; decreased ascites, renal vascular resistance, serum creatinine, and the release of renal tubular damage markers, including urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury moleculae-1 (uKim-1) in BDL-OCA rats. In the BDL group, inhibition of the renal oxidative stress (8-iso-PGF2α)-activated cyclooxygenase-thromboxane A2 [COX-TXA2] pathway, apoptosis, and tubular injury accompanied by a decrease in hyper-responsiveness to the vasoconstrictor 8-iso-PGF2α in perfused kidneys. In vitro experiments revealed that 8-iso-PGF2α induced oxidative stress, release of reactive oxygen species, and cell apoptosis, which were reversed by concomitant incubation with the FXR agonist.
Through the inhibition of renal 8-iso-PGF2α production and the down-regulation of the COX-TXA2 pathway, our study suggests that chronic OCA treatment can ameliorate the HRS in ascitic cirrhotic rats. Thus, OCA is an agent with antioxidative stress, antivasoconstrictive, antiapoptotic properties which benefit ascitic, cirrhotic rats with systemic, hepatic, and renal abnormalities.
背景/目的：本研究探讨了慢性治疗法尼醇 X 受体（FXR）激动剂奥贝胆酸（OCA）的潜力，OCA 可抑制与氧化应激相关的发病机制，在胆管结扎（BDL）后 6 周发展为肝肾综合征（HRS）的腹水肝硬化大鼠中。
在接受 2 周载体或 OCA 治疗的腹水 BDL 和假手术大鼠（假手术-OCA 和 BDL-OCA 组）以及 NRK-52E 细胞（大鼠肾小管上皮细胞）中测量全身、内脏和肾脏血液动力学和发病机制级联。
慢性 OCA 治疗可显著使门静脉高压、肾小球滤过率、尿量、肾血流量正常化；降低腹水、肾血管阻力、血清肌酐和肾小管损伤标志物的释放，包括尿中性粒细胞明胶酶相关脂质运载蛋白（uNGAL）和肾损伤分子 1（uKim-1）在 BDL-OCA 大鼠中。在 BDL 组中，抑制肾氧化应激（8-异前列腺素 F2α）-激活的环加氧酶-血栓素 A2 [COX-TXA2] 途径、细胞凋亡和管状损伤伴随着对灌注肾脏中血管收缩剂 8-异前列腺素 F2α的超反应性降低。体外实验表明，8-异前列腺素 F2α诱导氧化应激、活性氧物质的释放和细胞凋亡，这些都被 FXR 激动剂同时孵育所逆转。
通过抑制肾脏 8-异前列腺素 F2α的产生和下调 COX-TXA2 途径，我们的研究表明，慢性 OCA 治疗可以改善腹水肝硬化大鼠的 HRS。因此，OCA 是一种具有抗氧化应激、抗血管收缩、抗细胞凋亡作用的药物，有益于有全身、肝脏和肾脏异常的腹水、肝硬化大鼠。
