ISOPROSTANES IN LIVER DISEASE-INDUCED RENAL DYSFUNCTION

异前列腺素在肝病引起的肾功能障碍中的作用

• 批准号: 6634778
• 负责人: LUIS A. JUNCOS
• 金额: $ 12万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6634778
• 关键词: acetylcholine; angiotensin II; antioxidants; arachidonate; arterioles; cholanate compound; disease /disorder model; hemodynamics; kidney circulation; kidney circulation disorder; laboratory rat; liver disorder; molecular pathology; nitric oxide; nitroferricyanide; oxidative stress

DESCRIPTION (adapted from the application) Liver disease induces a spectrum of renal abnormalities. Early on there is redistribution of intrarenal RBF; that is there is cortical vasoconstriction with shunting of RBF towards the juxtamedullary nephrons, which may contribute to enhanced sodium and water retention. However, the mechanisms leading to these alterations are not clear. Recent studies have described a new family of prostaglandin-like compounds, F2-isoprostanes, that are formed in vivo by free-radical catalyzed peroxidation of arachidonic acid. These compounds are markers of oxidant injury, possess biological activity and are markedly elevated in liver disease. Yet their role in the associated renal dysfunction is poorly understood. We hypothesize that elevated oxidative stress in liver disease increases F2-isoprostanes, which in turn contribute to the altered renal hemodynamics. In our first aim, we examine whether oxidative stress via F2-isoprostanes contributes to the redistribution of intrarenal RBF induced by chronic bile duct ligation (c-BDL). The rationale for this aim is that c-BDL increases oxidative stress and causes redistribution of RBF. Thus, using micro-CT technology, we will examine whether by acutely or chronically blocking oxidative stress or the F2-isoprostanes receptor reverses or prevents the redistribution of RBF. The next aims assess the direct actions of isoprostanes, and what role oxidative stress via isoprostanes plays in the renal vascular abnormalities of the c-BDL rats. For this, we will study vascular reactivity in isolated microperfused afferent arterioles dissected from the superficial and juxtamedullary cortex (s-Af-Arts and jm-Af-Arts respectively), of control and c-BDL rats. In aim #2 we test the hypothesis that s-Af-Arts are more sensitive than jm-Af-Arts isoprostane-induced vasoconstriction, which thus may explain why renal medullary perfusion is preserved despite marked cortical hypoperfusion. In aim #3 we test the hypothesis that vascular reactivity of s-Af-Art but not jm-Af-Arts is enhanced in c-BDL compared to controls (contributing to the above-mentioned redistribution of RBF). If we find that Af-Art reactivity is altered, we will test the hypothesis that the enhanced reactivity is due to oxidative stress via increased isoprostanes by determining whether treatment with antioxidants or isoprostane antagonists improves the vascular parameters. Finally, because bile acids are very elevated in c-BDL, and can themselves promote oxidative stress, aim #4 tests the hypothesis that the elevated bile acids themselves contribute to the enhanced Af-Art reactivity via their pro-oxidant actions. We will examine the effects that bile acids have on s- and jm-Af-Art diameter, and reactivity (as in aim #2). This information will complement that obtained in aim #2 (where the exposure to bile acids is chronic in vivo rather than acute in vitro). Our proposed application therefore characterizes the renal vascular actions of oxidative stress and isoprostanes, and evaluates their role in the c-BDL rats.

描述（改编自应用程序） 肝脏疾病可引起一系列肾脏异常。早些时候， 肾内RBF的重新分布;即存在皮质血管收缩 RBF向延髓肾单位分流，这可能有助于 增加钠和水的保留。然而，导致 这些变化并不清楚。最近的研究描述了一个新的家庭， 前列腺素样化合物，F2-异前列腺素，在体内由 自由基催化的花生四烯酸过氧化反应。这些化合物 氧化损伤标志物，具有生物活性， 在肝病中升高。然而，它们在相关的肾功能障碍中的作用 是很难理解的。我们假设肝脏中氧化应激的升高 疾病增加F2-异前列腺素，这反过来又有助于改变 肾血流动力学在我们的第一个目标中，我们研究是否通过氧化应激， F2-异前列腺素有助于肾内RBF的重新分布 慢性胆管结扎（c-BDL）。这一目标的基本原理是， 增加氧化应激并引起RBF的重新分布。因此，使用 微CT技术，我们将检查是否通过急性或慢性阻塞 氧化应激或F2-异前列腺素受体逆转或阻止 RBF的再分配下一个目标是评估异前列烷的直接作用， 氧化应激通过异前列腺素在肾血管中起什么作用 c-BDL大鼠的异常。为此，我们将研究血管反应性， 分离微灌注的传入小动脉， 延髓皮质（分别为s-Af-Arts和jm-Af-Arts），对照组和 c-BDL大鼠。在目标#2中，我们测试了s-Af-Arts更敏感的假设 比jm-Af-Arts异前列腺素诱导的血管收缩，这可以解释 为什么尽管有明显的皮质 低灌注在目标3中，我们检验了以下假设： 与对照组相比，c-BDL中s-Af-Art而非jm-Af-Arts增强 （有助于上述RBF的再分配）。如果我们发现 Af-Art反应性改变，我们将测试增强的 反应性是由于氧化应激通过增加异前列腺素，通过测定 用抗氧化剂或异前列烷拮抗剂治疗是否改善了 血管参数最后，因为胆汁酸在c-BDL中非常高， 并且本身可以促进氧化应激，目标#4测试假设， 升高的胆汁酸本身有助于增强Af-Art反应性 通过它们的促氧化作用。我们将研究胆汁酸的作用 关于s-和jm-Af-Art直径和反应性（如在目标#2中）。这些信息 将补充目标#2中获得的结果（其中暴露于胆汁酸是 体内慢性而非体外急性）。因此，我们提出的申请 表征了氧化应激和异前列烷的肾血管作用， 并评价其在c-BDL大鼠中的作用。