Mathematical Model of Vascular and Tubular Transport in the Rat Outer Medulla

大鼠外延髓血管和肾小管运输的数学模型

• 批准号: 7623694
• 负责人: AURELIE EDWARDS
• 金额: $ 12.48万
• 依托单位: TUFTS UNIVERSITY MEDFORD
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623694
• 关键词: Accounting; Active Biological Transport; Affect; Angiotensin II; Antihypertensive Agents; Antioxidants; Architecture; Bilirubin; Biliverdine; Blood; Blood Circulation; Blood Vessels; Blood flow; Carbon Monoxide; Condition; Data; Diffusion; Elevation; Epithelium; Equilibrium; Erythrocytes; Excretory function; Generations; Heme; Hemoglobin; Hypoxia; Injury; Kidney; Limb structure; Mediating; Microcirculation; Modeling; Natriuresis; Nitric Oxide; Oxygen; Oxygen Consumption; Oxygenases; Perfusion; Pericytes; Physiological; Plasma Proteins; Play; Predisposition; Production; Rattus; Reactive Oxygen Species; Rectum; Regulation; Renal function; Role; Simulate; Sodium; Study models; Superoxides; System; Testing; Thick; Tubular formation; Urea; Vasodilation; Water; Work; base; inhibitor/antagonist; insight; kidney medulla; kidney vascular structure; mathematical model; paracrine; pressure; urinary

PROJECT SUMMARY The overall objective of the proposed work is to use mathematical modeling to gain fundamental insights into the mechanisms by which nitric oxide (NO), superoxide (O2 -), and heme oxygenase (HO) regulate renal medullary blood flow, oxygenation, and sodium reabsorption. We will develop numerical models, with inputs from experimental data, to investigate: (I) how NO and O2 - regulate medullary thick ascending limb (mTAL) active sodium reabsorption and oxygen consumption. We will develop a new, steady-state model of vascular and tubular transport in the rat outer medulla (OM), that accounts for the three-dimensional architecture of the medulla, the presence of red blood cells, as well as the production and consumption of oxygen, NO and O2 -. We will determine how interactions between NO and O2 - affect mTAL sodium reabsorption under physiological and pathological conditions. We will examine the hypothesis that NO, as an endogenous inhibitor of active transport, plays an important role in modulating the susceptibility of the medulla to anoxic injury. (II) how NO and O2 - regulate medullary blood flow, blood distribution, and oxygen supply. We will convert the new steady-state model into a dynamic model, and incorporate the effects of vasodilation on medullary blood flow (MBF). We will examine the hypothesis that the diffusion of paracrine substances such as NO from adjacent tubules to vasa recta pericytes provides an efficient mechanism whereby local perfusion is precisely matched to tubular oxygen demand. We will determine whether the enhancement of NO generation that is mediated by constrictors of the medullary circulation (such as Angiotensin II) may serve to protect the outer medulla from ischemic injury. (III) how renal medullary heme oxygenase (HO) and its products carbon monoxide (CO) and biliverdin modulate tubular sodium reabsorption and medullary blood flow. Recent evidence suggests that the renal medullary HO/CO system constitutes a significant antihypertensive mechanism. We will incorporate into our model the activity of HO, the formation of its products, and their effects on reactive oxygen species and NO. We will examine the hypothesis that significant expression of HO in the renal medulla serves to protect this region from ischemic injury, through CO-induced vasodilation and bilirubin-mediated antioxidant effects. We will simulate the effects of renal perfusion pressure-induced elevations in medullary CO concentrations on mTAL sodium reabsorption, so as to gain some insight into the mechanisms underlying pressure natriuresis.

项目概要 拟议工作的总体目标是使用数学建模来获得基本见解 一氧化氮 (NO)、超氧化物 (O2) -) 和血红素加氧酶 (HO) 调节肾脏 髓质血流量、氧合和钠重吸收。我们将开发数值模型，并输入 根据实验数据，调查： (一)NO和O2如何 - 调节髓质厚升肢（mTAL）主动钠重吸收和 氧气消耗量。我们将开发一种新的大鼠血管和肾小管运输的稳态模型 外髓质（OM），它解释了髓质的三维结构，红色的存在 血细胞，以及氧气、NO 和 O2 的产生和消耗 -.我们将决定如何 NO 和 O2 之间的相互作用 - 影响生理和病理下mTAL钠的重吸收 状况。我们将检验以下假设：NO 作为主动转运的内源性抑制剂，在 在调节髓质对缺氧损伤的敏感性中发挥重要作用。 (二)NO和O2如何 - 调节髓质血流、血液分布和氧气供应。我们将 将新的稳态模型转换为动态模型，并考虑血管舒张的影响 髓质血流量（MBF）。我们将检验以下假设：旁分泌物质的扩散，例如 NO 从邻近小管到直肠血管周细胞提供了一种有效的机制，通过该机制局部灌注 与管状需氧量精确匹配。我们将确定NO生成是否增强 由髓质循环收缩剂（如血管紧张素 II）介导的作用可能有助于保护 外髓质因缺血性损伤。 （三）肾髓质血红素加氧酶（HO）及其产物一氧化碳（CO）和胆绿素如何 调节肾小管钠重吸收和髓质血流量。最近的证据表明，肾 髓质H2O/CO系统构成重要的降压机制。我们将纳入我们的 模拟 H2O 的活性、其产物的形成及其对活性氧和 NO 的影响。 我们将检验肾髓质中 H2O 的显着表达有助于保护这一假设的假设。 通过 CO 诱导的血管舒张和胆红素介导的抗氧化作用，使该区域免受缺血性损伤。我们 将模拟肾灌注压引起的髓质 CO 浓度升高的影响 mTAL 钠重吸收，以便深入了解压力尿钠的机制。