A computational model of epithelial solute and water transport along a human nephron
A computational model of epithelial solute and water transport along a human nephron
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DOI：
10.1371/journal.pcbi.1006108
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发表时间：
2019-02-01
影响因子：
4.3
通讯作者：
Layton, Harold E.
中科院分区：
文献类型：
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作者：
Layton, Anita T.;Layton, Harold E.
我们已经开发了第一个计算模型的溶质和水的运输从鲍曼空间的乳头状尖端的人肾的肾单位。肾单位表现为一个由一层上皮细胞排列的小管，其顶端和基底侧转运蛋白根据细胞类型而变化。该模型是制定为稳定状态，并由一个大的系统耦合常微分方程和代数方程。模型的解决方案描述了管腔流体流量，静水压力，管腔流体溶质浓度，细胞溶质浓度，上皮膜电位，跨细胞和细胞旁通量。我们发现，如果我们假设转运蛋白密度和渗透性在人和大鼠肾单位之间是相同的（除了沿着近端小管的葡萄糖转运蛋白沿着和沿着集合管的H+泵沿着），该模型产生与人体数据一致的体积和关键溶质的节段递送和尿排泄。该模型预测，人类肾单位表现出肾小球肾小管平衡，近端肾小管Na+重吸收与单肾单位肾小球滤过率成比例变化。为了模拟新型糖尿病治疗的作用，我们抑制了近曲小管的Na+-葡萄糖协同转运蛋白2（SGLT 2）沿着。模拟结果预测，段的Na+重吸收显着下降，导致钠尿和渗透性diurethrits.Author摘要除了众所周知的功能，废物从身体中清除，肾脏也负责身体的盐，钾，酸含量和血压的关键调节。肾脏执行这些维持生命的任务，每24小时过滤并返回血液约200夸脱。没有回到血液中的物质会以尿液的形式排出体外。尿的产生涉及高度复杂的分泌和重吸收步骤。为了在不采用侵入性实验程序的情况下研究这些过程，我们开发了人类肾单位（肾脏的功能单位）的第一个计算模型。该模型包含了在形成肾单位壁的上皮细胞中发生的运输过程的详细表示。使用该模型，我们进行了模拟，以预测有多少过滤的溶质和水被运输沿着每个人和功能不同的肾单位部分。我们在正常生理条件下和药理条件下进行了这些模拟。肾单位模型可用作人体肾功能综合模型的重要组成部分。
We have developed the first computational model of solute and water transport from Bowman space to the papillary tip of the nephron of a human kidney. The nephron is represented as a tubule lined by a layer of epithelial cells, with apical and basolateral transporters that vary according to cell type. The model is formulated for steady state, and consists of a large system of coupled ordinary differential equations and algebraic equations. Model solution describes luminal fluid flow, hydrostatic pressure, luminal fluid solute concentrations, cytosolic solute concentrations, epithelial membrane potential, and transcellular and paracellular fluxes. We found that if we assume that the transporter density and permeabilities are taken to be the same between the human and rat nephrons (with the exception of a glucose transporter along the proximal tubule and the H+-pump along the collecting duct), the model yields segmental deliveries and urinary excretion of volume and key solutes that are consistent with human data. The model predicted that the human nephron exhibits glomerulotubular balance, such that proximal tubular Na+ reabsorption varies proportionally to the single-nephron glomerular filtration rate. To simulate the action of a novel diabetic treatment, we inhibited the Na+-glucose cotransporter 2 (SGLT2) along the proximal convoluted tubule. Simulation results predicted that the segment's Na+ reabsorption decreased significantly, resulting in natriuresis and osmotic diuresis.Author summary In addition to its well-known function of waste removal from the body, the kidney is also responsible for the critical regulation of the body's salt, potassium, acid content, and blood pressure. The kidneys perform these life-sustaining task by filtering and returning to blood stream about 200 quarts of blood every 24 hours. What isn't returned to blood stream is excreted as urine. The production of urine involves highly complex steps of secretion and reabsorption. To study these processes without employing invasive experimental procedures, we developed the first computational model of the human nephron (which is the functional unit of a kidney). The model contains detailed representation of the transport processes that take place in the epithelial cells that form the walls of the nephron. Using that model, we conducted simulations to predict how much filtered solutes and and water is transported along each individual and functionally distinct nephron segment. We conducted these simulations under normal physiological conditions, and under pharmacological conditions. The nephron model can be used as an essential component in an integrated model of kidney function in humans.