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

项目摘要 拟议工作的总体目标是使用数学建模，以获得基本的见解， 一氧化氮（NO）、超氧化物（O2 血红素加氧酶（HO）调节肾脏 髓质血流、氧合和钠重吸收。我们将开发数字模型， 根据实验数据，研究： (I)NO和O2 - 调节髓质粗升支（mTAL）活性钠重吸收， 耗氧量我们将建立一种新的大鼠血管和肾小管转运的稳态模型 外髓质（OM），它解释了髓质的三维结构，红细胞的存在， 血细胞，以及氧气，NO和O2的生产和消耗 -.我们将决定如何 NO和O2相互作用 - 在生理和病理条件下影响mTAL钠重吸收 条件我们将检验一氧化氮作为主动转运的内源性抑制剂， 在调节延髓对缺氧损伤的敏感性中起重要作用。 (II)NO和O2 - 调节髓血流量、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，并将血管舒张对 髓质血流量（MBF）。我们将检验这样的假设，即旁分泌物质的扩散， NO从邻近小管到直小血管周细胞提供了一种有效的机制， 精确地匹配管状氧气需求。我们将确定NO生成的增强是否 由延髓循环的收缩物（如血管紧张素II）介导的这种抑制作用可能有助于保护 外髓质缺血性损伤。 (III)肾髓质血红素氧合酶（HO）及其产物一氧化碳（CO）和胆绿素 调节肾小管钠重吸收和髓质血流。最近的证据表明，肾脏 延髓HO/CO系统是重要的降压机制。我们将把它纳入我们的 模拟HO的活性，其产物的形成，以及它们对活性氧和NO的影响。 我们将检验这一假设，即肾髓质中HO的显著表达有助于保护这一点。 通过一氧化碳诱导的血管舒张和胆红素介导的抗氧化作用，我们 将模拟肾灌注压诱导的髓质CO浓度升高对 mTAL钠重吸收，以便深入了解压力钠尿作用的机制。

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.