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: 7645459
• 负责人: AURELIE EDWARDS
• 金额: $ 19.84万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645459
• 关键词: 3-Dimensional; Accounting; Active Biological Transport; Affect; Angiotensin II; Antihypertensive Agents; Antioxidants; Architecture; Bilirubin; Biliverdine; Blood; Blood Circulation; Blood Pressure; Blood Vessels; Blood flow; Caliber; Carbon Monoxide; Data; Diffusion; Epithelium; Equilibrium; Erythrocytes; Excretory function; Generations; Heme; Hemoglobin; Hypertension; Hypoxia; Injury; Kidney; Kidney Diseases; Lead; Limb structure; Mediating; Microcirculation; Modeling; Natriuresis; Nitric Oxide; Oxygen; Oxygen Consumption; Oxygenases; Perfusion; Pericytes; Physiological; Plasma Proteins; Play; Predisposition; Production; Public Health; Rattus; Reactive Oxygen Species; Rectum; Regulation; Renal function; Research; Role; Simulate; Slice; Sodium; Sodium Chloride; 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; public health relevance; two-dimensional; urinary

DESCRIPTION (provided by applicant): 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 the activity of HO, the formation of its products, and their effects on reactive oxygen species and NO, first into a two- dimensional, steady-state model of the rat OM, then into the newly developed, three-dimensional, dynamic model. 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. PUBLIC HEALTH RELEVANCE: The objective of this proposal is to provide a better understanding of the mechanisms by which nitric oxide (NO), superoxide (O2-), and heme oxygenase (HO) regulate blood flow, oxygenation and sodium reabsorption in the renal medulla. This research is relevant to public health because NO, O2-, and HO all play an important role in the regulation of salt and water excretion by the kidney, and in the long-term control of arterial blood pressure. A shift in the balance between NO, O2-, and HO can lead to the progression of renal disease and hypertension.

描述（由申请人提供）：拟议工作的总体目标是使用数学模型来深入了解一氧化氮（NO）、超氧化物（O2-）和血红素加氧酶（HO）调节肾髓质血液的机制流量、氧合和钠重吸收。我们将根据实验数据开发数值模型，以研究：(I) NO 和 O2 如何调节髓质厚升肢 (mTAL) 活性钠重吸收和耗氧量。我们将开发一种新的大鼠外髓质（OM）血管和肾小管运输的稳态模型，该模型解释了髓质的三维结构、红细胞的存在以及红细胞的产生和消耗氧气、NO 和 O2-。我们将确定生理和病理条件下 NO 和 O2- 之间的相互作用如何影响 mTAL 钠重吸收。我们将检验这样的假设：NO 作为主动转运的内源性抑制剂，在调节髓质对缺氧损伤的敏感性中发挥着重要作用。 （二）NO和O2-如何调节髓质血流、血液分布和供氧。我们将把新的稳态模型转换为动态模型，并考虑血管舒张对髓质血流（MBF）的影响。我们将检验以下假设：旁分泌物质（例如 NO）从邻近肾小管扩散到直肠血管周细胞提供了一种有效机制，使局部灌注与肾小管需氧量精确匹配。我们将确定由髓质循环收缩剂（例如血管紧张素 II）介导的 NO 生成的增强是否可以起到保护外髓质免受缺血性损伤的作用。 （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。最近的证据表明肾髓质 HO/CO 系统构成了重要的抗高血压机制。我们将首先将 H2O 的活性、其产物的形成及其对活性氧和 NO 的影响纳入大鼠 OM 的二维稳态模型中，然后纳入新开发的三维、动态模型。我们将检验这样的假设：肾髓质中 H2O 的显着表达通过 CO 诱导的血管舒张和胆红素介导的抗氧化作用来保护该区域免受缺血性损伤。我们将模拟肾灌注压力引起的髓质 CO 浓度升高对 mTAL 钠重吸收的影响，以便深入了解压力尿钠的机制。公共健康相关性：本提案的目的是更好地了解一氧化氮 (NO)、超氧化物 (O2-) 和血红素加氧酶 (HO) 调节肾髓质血流、氧合和钠重吸收的机制。这项研究与公众健康相关，因为 NO、O2- 和 H2O 在肾脏调节盐和水排泄以及长期控制动脉血压方面都发挥着重要作用。 NO、O2- 和 H2O 之间平衡的变化可能导致肾脏疾病和高血压的进展。