Flow-stimulated endocytosis in the proximal tubule

描述（由申请人提供）：肾近端小管（PT）是离子、溶质和过滤低分子量（LMW）蛋白质重吸收的主要部位。PT细胞对伴随肾小球滤过率改变的流体剪切应力（FSS）变化作出反应，对离子转运能力进行急性调节。本研究的重点是了解PT细胞是否也会根据需求的改变调整巨噬细胞素和立方蛋白介导的LMW蛋白内吞能力。这些蛋白摄取缺陷导致小管性蛋白尿，最终可导致肾功能衰竭。我们发现，PT细胞暴露于FSS后，巨噬蛋白/立方蛋白配体白蛋白以及液相标记物的顶端内噬作用显着增加。此外，初级纤毛是这种反应所必需的。本提案的目的是：(1)确定FSS的变化如何被转导到对根尖内吞作用的影响；(2)确定在Lowe综合征（一种可能涉及纤毛发生缺陷的X连锁疾病）的动物模型中观察到的血流依赖性内吞作用的缺陷调节是否有助于LMW蛋白尿。我们已经组建了一支优秀的研究团队，他们具有必要的专业知识来开展这一广泛的研究。我们的实验结果将为新发现的在维持肾脏功能中起重要作用的途径提供关键信息。

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.