Flow-stimulated endocytosis in the proximal tubule

性状（由申请方提供）：肾脏近端小管（PT）是重吸收离子、溶质和滤过的低分子量（LMW）蛋白的主要部位。PT细胞对伴随肾小球滤过率改变的流体切应力（FSS）变化作出反应，从而急性调节离子转运能力。该建议的重点是了解PT细胞是否也调整巨蛋白和cubilin介导的低分子量蛋白的内吞作用的能力，以响应改变的需求。这些蛋白质的摄取不足会导致肾小管蛋白尿，最终导致肾衰竭。我们已经发现，顶端内吞的megalin/cubilin配体白蛋白以及流体相标志物后，PT细胞暴露于FSS显着增加。此外，初级纤毛需要这种反应。本提案的目的是（1）确定FSS的变化如何转化为对顶端内吞作用的影响，以及（2）确定流量依赖性内吞作用的缺陷性调节是否有助于在Lowe综合征动物模型中观察到的LMW蛋白尿，Lowe综合征是一种可能涉及纤毛发生缺陷的X连锁疾病。我们已经组建了一个优秀的研究团队，他们拥有必要的专业知识来开展这一广泛的研究。我们的实验结果将提供有关新发现的在维持肾功能中起重要作用的途径的关键信息。

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.