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

项目总结 拟议工作的总体目标是使用数学建模来获得对 一氧化氮(NO)、超氧化物歧化酶(O2)的作用机制 -)，和血红素加氧酶(HO)调节肾脏 髓质血流、氧合和钠重吸收。我们将开发具有输入的数值模型 从实验数据中，调查： (I)NO和O2如何 -调节髓质粗大上肢(MTAL)主动钠重吸收和 耗氧量。我们将在大鼠体内建立一种新的稳态血管和肾小管运输模型 外髓(OM)，它解释了延髓的三维结构，红色的存在 血细胞，以及氧气、一氧化氮和氧气的产生和消耗 -。我们将决定如何 NO和O2之间的相互作用 -生理和病理条件下对mTAL钠重吸收的影响 条件。我们将检验这样一种假设，即作为主动转运的内源性抑制物，NO在 在调节延髓对缺氧损伤的敏感性中起重要作用。 (Ii)NO和O2如何 --调节骨髓血流量、血液分布和氧气供应。我们会 将新的稳态模型转换为动态模型，并考虑血管扩张对 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 从相邻小管到直肠血管周细胞的NO提供了一种有效的机制，通过这种机制，局部灌流 与管状需氧量精确匹配。我们将确定是否增强NO生成 这是由髓循环的缩窄器(如血管紧张素II)介导的，可能有助于保护 缺血损伤所致的外髓质。 (Iii)肾髓质血红素加氧酶(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量。最近的证据表明，肾脏 延髓HO/CO系统构成了一个重要的降压机制。我们将合并到我们的 模拟HO的活性，其产物的形成，以及它们对活性氧物种和NO的影响。 我们将检验一种假说，即肾脏髓质中HO的显著表达起到保护作用。 通过一氧化碳诱导的血管扩张和胆红素介导的抗氧化作用，减轻缺血区域的损伤。我们 将模拟肾灌流压力引起的髓内一氧化碳浓度升高对 MTAL钠重吸收，从而对压力性钠尿的机制有一定的了解。

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.