Development of a computational biomechanics model of the glomerulus to assess risk of mechanical stress-induced glomerular injury in conditions of reduced afferent arteriole vasoconstrictive response.

项目摘要/摘要 传入小动脉的血管收缩反应性相对于灌流压的降低是 与糖尿病、某些形式的高血压和慢性肾脏的肾小球损害的进展有关 涉及功能性肾单位丧失的疾病。血管收缩反应性的降低 传入小动脉增加传入血流量和肾小球内压，据信这会增加 对肾小球细胞施加的机械应力(循环拉伸和流体流动剪应力)。响应于循环 拉伸，系膜细胞增加细胞外基质(ECM)成分的沉积，足细胞可能 从肾小球毛细血管分离。为了应对增加的剪应力，血管内皮细胞增加 炎症标志物的产生。这些结果共同表明，血管收缩功能减弱 传入小动脉对灌流压的反应性通过以下途径引起肾小球细胞损伤 增加肾小球毛细血管壁上的剪应力和循环拉伸。尽管机械应力- 诱发性肾小球损伤是肾脏疾病研究中一个被普遍接受的概念，其实际程度 机械应力，特别是由弱化的传入小动脉引起的剪切应力和环应力 血管收缩反应，都是未知的。这项提议的总体目标是使用多尺度数学 估计肾小球毛细血管内切应力和毛细血管壁伸展大小的模型 由于传入小动脉血管收缩反应性降低而形成的网络。我们将开发一种 “肾小球网络模型”，计算实际的、解剖学上准确的 肾小球微血管网络。传入小动脉阻力的反馈模型将与 在我们的模型中，肾小球网络模型代表了肾脏自动调节的复杂动力学。 此外，我们还将开发单个肾小球毛细血管的计算流体动力学(CFD)模型， 考虑到在可渗透通道中流动的弹性红细胞结构所引起的动力学。 采用多尺度数学建模方法，针对肾小球网络的每个毛细血管段 模型中，肾小球网络模型的输出将映射到CFD毛细血管模型中的参数，以 计算容器壁上的剪应力。使用此方法计算的机械应力将为 与先前细胞研究的实验参数相比较以确定肾小球细胞损伤的风险 有无传入小动脉减少引起的病理血流动力学状况 血管收缩反应性。这项工作将作为肾小球损伤风险指数的基础 病理的肾脏血流动力学状况，并将为“芯片上的肾小球”的设计提供信息 微生理系统。众所周知，机械力对这些系统的效果有至关重要的影响，因为 疾病模型和药物测试平台；因此，拟议的项目将有助于开发和 建立适用于这些使用环境的这些系统。

Project Summary/Abstract A reduction in the vasoconstrictive responsiveness of the afferent arteriole relative to perfusion pressure is implicated in the progression of glomerular injury in diabetes, some forms of hypertension and chronic kidney diseases involving the loss of functional nephrons. A reduction of the vasoconstrictive responsiveness of the afferent arteriole raises afferent blood flow and intraglomerular pressure which is believed to increase mechanical stress (cyclic stretch and fluid flow shear stress) on the glomerular cells. In response to cyclic stretch, mesangial cells increase deposition of extracellular matrix (ECM) components and podocytes may detach from the glomerular capillary. In response to increased shear stress, vascular endothelial cells increase production of inflammatory markers. These results collectively indicate that a reduced vasoconstrictive responsiveness of the afferent arteriole relative to perfusion pressure causes injury of glomerular cells by increasing shear stress on and cyclic stretch of the glomerular capillary walls. Although mechanical stress- induced glomerular injury is a generally accepted concept in kidney disease research, the actual magnitudes of mechanical stress, in particular shear stress and hoop stress resulting from an attenuated afferent arteriole vasoconstrictive response, are unknown. The overall aim of this proposal is to use multiscale mathematical modeling to estimate the magnitudes of shear stress and capillary wall stretch in the glomerular capillary network as a result of decreased afferent arteriole vasoconstrictive responsiveness. We will develop a “glomerular network model” that calculates flows through the capillaries of an actual, anatomically-accurate glomerular microvascular network. A feedback model of afferent arteriole resistance will be integrated with the glomerular network model to represent the complex dynamics of renal autoregulation in our model. Additionally, we will develop a computational fluid dynamics (CFD) model of a single glomerular capillary, taking into account the dynamics arising from elastic red blood cell structures flowing in a permeable channel. Taking a multiscale mathematical modeling approach, for each capillary segment of the glomerular network model, output of the glomerular network model will be mapped to parameters in the CFD capillary model to calculate shear stresses on the vessel walls. The mechanical stresses calculated using this approach will be compared to experimental parameters of previous cell studies to determine the risk of glomerular cell injury with and without the pathological hemodynamic conditions arising from reduction in afferent arteriole vasoconstrictive responsiveness. This work will serve as a basis for a glomerular injury risk index in pathological renal hemodynamic conditions and will inform the design of “glomerulus-on-a-chip” microphysiological systems. Mechanical forces are known to crucially affect the efficacy of these systems as models of disease and as drug testing platforms; thus, the proposed project will contribute to development and establishment of these systems for these contexts of use.