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。我们将开发数值模型，以实验数据为输入，研究：(I)NO和O2-如何调节髓质粗升支(MTAL)活性的钠重吸收和氧气消耗。我们将开发一种新的、稳态的大鼠外髓(OM)血管和小管运输模型，该模型解释了延髓的三维结构、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mTAL钠的重吸收。我们将检验这一假说，即NO作为主动运输的内源性抑制物，在调节延髓对缺氧损伤的敏感性方面发挥着重要作用。(Ii)NO和O2-如何调节骨髓血流量、血液分布和氧气供应。我们将把新的稳态模型转换为动态模型，并考虑血管扩张对骨髓血流量(MBF)的影响。我们将检验这样一种假设，即NO等旁分泌物质从相邻小管扩散到直肠血管周细胞提供了一种有效的机制，使局部灌流与肾小管氧需求精确匹配。我们将确定由髓循环收缩因子(如血管紧张素II)介导的NO生成增加是否有助于保护外髓免受缺血损伤。(Iii)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。我们将把HO的活性，其产物的形成，以及它们对活性氧和NO的影响，首先纳入大鼠OM的二维稳态模型，然后进入新开发的三维动态模型。我们将通过CO诱导的血管扩张和胆红素介导的抗氧化作用来检验这一假设，即HO在肾髓质中的显著表达有助于保护该区域免受缺血损伤。我们将模拟肾灌流压力引起的髓内CO浓度升高对mTAL钠重吸收的影响，以期深入了解压力性钠尿的机制。与公共健康相关：这项建议的目的是为了更好地了解一氧化氮(NO)、超氧化物(O2-)和血红素加氧酶(HO)调节肾脏髓质的血流、氧合和钠重吸收的机制。这项研究与公众健康有关，因为NO、O2-和HO在肾脏调节盐分和水分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HO之间平衡的改变可能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.