Model of Transport in Renal Medullary Microvasculature

描述(申请人提供)：肾髓质的微循环在调节液体和电解质的排泄以及长期维持动脉血压方面起着至关重要的作用。这项研究的总体目标是扩展我们的肾脏髓质微循环的数学模型，以了解特定的转运体、渗透激素和激素对髓质血流及其分布的影响。我们的具体目标如下： 目的1：确定UTB尿素转运体在提供容量外流途径中的重要性，该途径将直肠降血管(DVR)的血流量分流到直肠血管的上行(AVR)，继而减少流向延髓内侧的血流量。我们将把新的体外发现(包括UTB基因敲除小鼠的通透性和反射系数测量)纳入我们的数学模型，以检查水通道和尿素转运体在调节流向内髓的血液中的作用。 目的：研究溶质通透性对血流速度的影响。DVR对钠和棉子糖的通透性随灌注率的不同而变化；这种依赖关系可能通过NO的产生来调节。我们将研究血流依赖性的通透性增加是否会降低跨壁浓度梯度，从而减少水从DVR流出，从而增加流向髓质内侧的血流量，降低浓缩能力。 目的3：确定乳酸在骨髓微循环中是否起重要作用。有人认为，乳酸的积累可以增加细降肢的水分排出，并使数学模型能够准确地预测皮质-髓质渗透压梯度。我们将研究乳酸的存在是否可以增加DVR跨细胞途径的体积外流，从而影响流向乳头和轴向小溶质浓度梯度的血流。 目的：观察一氧化氮对延髓整体血流量的影响，以及对内髓和外髓束间区血流分布的影响。我们将调查没有一代人可以消除髓质缺氧的程度，以及粗大的上肢产生的一氧化氮是否可以构成一个反馈系统，旨在专门保护mTAL免受缺血损伤，从而损害内髓。

DESCRIPTION (provided by applicant): The microcirculation in the renal medulla plays an essential role in the regulation of fluid and electrolyte excretion and in the long-term maintenance of arterial blood pressure. The overall goal of this research is to extend our mathematical model of the renal medullary microcirculation in order to understand the effects of specific transporters, osmolytes and hormones on medullary blood flow and its distribution. Our specific aims are as follows: Aim 1: To determine the importance of UTB urea transporters in providing a route for volume efflux that shunts blood flow from descending vasa recta (DVR) to ascending vasa recta (AVR), secondarily reducing blood flow to the inner medulla. We will incorporate new in vitro findings (including permeability and reflection coefficient measurements in UTB knockout mice) into our mathematical model in order to examine the role of water channels and urea transporters in regulating blood flow to the inner medulla. Aim 2: To examine the effects of the dependence of solute permeability on blood flow rate. Permeability of DVR to sodium and raffinose varies with perfusion rate; this dependence may be mediated by NO generation. We will investigate whether flow dependent increases in permeability reduce transmural concentration gradients and therefore water efflux from DVR, thereby enhancing blood flow to the inner medulla and decreasing concentrating ability. Aim 3: To determine whether lactate plays a significant role in the medullary microcirculation. It has been suggested that the accumulation of lactate could augment water removal from the thin descending limb and enable mathematical models to accurately predict cortico-medullary osmolality gradients. We will examine whether the presence of lactate can enhance volume efflux from DVR across transcellular pathways, thereby affecting blood flow to the papilla and axial small solute concentration gradients. Aim 4: To examine the effect of nitric oxide on overall medullary blood flow as well as on the distribution of blood flow between the inner medulla and the interbundle region of the outer medulla. We will investigate the extent to which NO generation may abrogate medullary hypoxia, and whether the production of nitric oxide by the thick ascending limb could constitute a feedback system aimed at specifically protecting the mTAL from ischemic injury, to the detriment of the inner medulla.