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

描述（由申请人提供）：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（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。我们将开发数值模型，从实验数据的输入，调查：（I）如何NO和O2-调节髓厚升支（mTAL）的主动钠重吸收和氧消耗。我们将开发一个新的，稳态模型的血管和肾小管运输在大鼠外髓质（OM），占的三维结构的髓质，红细胞的存在，以及生产和消耗的氧气，NO和O2-。我们将确定NO和O2-之间的相互作用如何影响mTAL钠重吸收的生理和病理条件下。我们将研究的假设，NO，作为一种内源性抑制剂的主动运输，在调制的延髓缺氧损伤的易感性中起着重要的作用。(II)NO和O2如何调节髓质血流、血液分布和氧供应。我们将把新的稳态模型转换为动态模型，并将血管舒张对髓质血流（MBF）的影响。我们将研究的假设，如NO的旁分泌物质的扩散，从相邻的小管到直小血管周细胞提供了一个有效的机制，使局部灌注精确匹配肾小管的氧需求。我们将确定是否增强一氧化氮生成介导的缩窄的髓循环（如血管紧张素II）可能有助于保护外髓缺血性损伤。(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系统构成了一个重要的抗高血压机制。我们将纳入HO的活动，其产品的形成，以及它们对活性氧和NO的影响，首先进入大鼠OM的二维稳态模型，然后进入新开发的三维动态模型。我们将研究这一假设，即在肾髓质HO的显着表达，以保护这一地区的缺血性损伤，通过CO诱导的血管舒张和胆红素介导的抗氧化作用。我们将模拟肾脏灌注压引起的髓质CO浓度升高对mTAL钠重吸收的影响，从而深入了解压力性尿钠排泄的机制。公共卫生相关性：本研究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。NO、O2-和HO在肾脏对盐和水的排泄的调节以及动脉血压的长期控制中均发挥重要作用，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。

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.