Flow-stimulated endocytosis in the proximal tubule

描述(申请人提供)：肾脏的近端小管(PT)是离子、溶质和过滤的低分子量(LMW)蛋白质的主要重吸收部位。随着肾小球滤过率的改变，PT细胞能敏锐地调节离子转运能力，以响应流体切应力(FSS)的变化。这一建议的重点是了解PT细胞是否也调整巨蛋白和立方体蛋白介导的低分子蛋白内吞能力，以响应改变的需求。这些蛋白的摄取缺陷会导致小管性蛋白尿，最终可能导致肾功能衰竭。我们发现，当PT细胞暴露于FSS时，megalin/cubilin配体白蛋白以及液体相标志物的顶端内吞作用显着增加。此外，这种反应还需要初级纤毛。这项建议的目的是(1)确定FSS的变化如何转化为对心尖内吞作用的影响，以及(2)确定血流依赖性内吞作用的缺陷调节是否有助于在Lowe综合征动物模型中观察到的LMW蛋白尿，Lowe综合征是一种X连锁疾病，可能涉及纤毛发生缺陷。我们已经组建了一支具有基本专业知识的优秀调查团队，以开展这一广泛的研究。我们的实验结果将提供关于一种新发现的途径的关键信息，该途径在维持肾功能方面起着至关重要的作用。

DESCRIPTION (provided by applicant): The proximal tubule (PT) of the kidney is the primary site for reabsorption of ions, solutes, and filtered low molecular weight (LMW) proteins. PT cells acutely modulate ion transport capacity in respond to changes in fluid shear stress (FSS) that accompany alterations in glomerular filtration rate. This proposal is focused on understanding whether PT cells also adjust the capacity of megalin-and cubilin- mediated endocytosis of LMW proteins in response to altered demand. Defective uptake of these proteins leads to tubular proteinuria, which can eventually lead to renal failure. We have discovered that apical endocytosis of the megalin/cubilin ligand albumin as well as fluid phase markers is markedly increased upon exposure of PT cells to FSS. Moreover, primary cilia are required for this response. The aims of this proposal are to (1) determine how changes in FSS are transduced into effects on apical endocytosis and (2) determine whether defective modulation of flow-dependent endocytosis contributes to LMW proteinuria observed in animal models for Lowe Syndrome, an X- linked disorder that may involve defects in ciliogenesis. We have assembled an outstanding team of investigators with essential expertise to carry out this broad range of studies. The results of our experiments will provide key information about a newly discovered pathway that plays an essential role in maintaining kidney function.