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High Resolution Reconstruction of the Proximal Tubule Apical Endocytic Pathway

Physiology(2024)

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摘要
Kidney proximal tubule (PT) cells are specialized for effcient apical uptake of albumin and other proteins that escape the glomerular filtration barrier. The apical endocytic pathway is uniquely organized to maintain highly dynamic retrieval of these proteins via binding to the multiligand receptors megalin and cubilin. Ultrastructural studies following the fate of internalized markers have provided a temporal model for the delivery of receptor-bound ligands and fluid phase markers to lysosomes. In this model, internalization from the apical membrane occurs via budding of irregular clathrin-coated invaginations that form at the base of microvilli. After uncoating, budded vesicles fuse with apical early endosomes (AEEs) where acidification triggers dissociation of ligands from their receptors. AEEs further mature and expand into apical vacuoles (AVs) that ultimately deliver ligands and fluid to lysosomes. Receptor recycling to the apical membrane is thought to occur via dense apical tubules (DATs) that have a uniform diameter and membrane thickness and which appear to bud from both AEEs and AVs. We used Zeiss Arivis Pro technology to annotate and reconstruct apical membrane invaginations and endocytic compartments in a 3D volume of mouse kidney with isotropic voxels of 4 nm, acquired using focused ion-beam scanning electron microscopy (FIB-SEM). Strikingly, 3D reconstruction of DATs revealed a large and highly interconnected network of tubules in the subapical region of PT cells. Connections were observed between the DAT network and endosomal compartments, as well as between DATs and apical membrane invaginations. Our data suggest the possibility that DATs exist as a stable compartment that interacts transiently with the apical membrane to enable receptor recycling. Current studies are underway to better understand how PT cells modulate endocytic entry and recycling via the same portals. National Institute of Health: 5T32GM133353-03, R01 DK118726, R01 DK125049, U54 DK137329. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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