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获得对一氧化氮（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的基本见解。我们将根据实验数据建立数值模型来研究：(1)NO和O2如何调节髓质厚升肢（mTAL）活性钠重吸收和氧消耗。我们将在大鼠外髓质（OM）中建立一个新的、稳态的血管和管状运输模型，该模型考虑了髓质的三维结构、红细胞的存在以及氧、NO和O2-的产生和消耗。我们将确定在生理和病理条件下NO和O2-之间的相互作用如何影响金属钠的重吸收。我们将检验NO作为内源性主动转运抑制剂在调节髓质对缺氧损伤的易感性中起重要作用的假设。（II） 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，并纳入血管舒张对髓质血流（MBF）的影响。我们将检验旁分泌物质（如NO）从邻近小管向血管直血管周细胞的扩散提供了一种有效的机制，即局部灌注与小管需氧量精确匹配。我们将确定髓质循环收缩剂（如血管紧张素II）介导的一氧化氮生成的增强是否有助于保护外髓质免受缺血性损伤。（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系统构成了一个重要的降压机制。我们将首先将HO的活性、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，然后将其纳入新开发的三维动态模型。我们将检验这样一种假设：通过co诱导的血管舒张和胆红素介导的抗氧化作用，HO在肾髓质中的显著表达有助于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浓度升高对金属钠重吸收的影响，从而深入了解压力性钠尿的机制。公共卫生相关性：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）调节肾髓质的血流、氧合和钠重吸收的机制。NO、O2-和HO在调节肾脏的盐和水排泄以及长期控制动脉血压中都起着重要作用，因此本研究与公共卫生有关。NO， O2-和HO之间平衡的改变可导致肾脏疾病和高血压的进展。