Abstract
The proximal tubule maintains a robust endocytic pathway that is necessary for the recovery of proteins and vitamins from the ultrafiltrate and for the rapid regulation of ion transport. The large multiligand receptor megalin is essential to this process. In the absence of functional megalin, membrane and fluid flux through endocytic compartments is profoundly compromised, whereas the binding of filtered drugs to megalin is a major cause of nephrotoxicity. Insights into the structure of megalin offers clues as to how megalin might drive endocytic dynamics through pH-dependent conformational rearrangements, and findings from focused ion beam-scanning electron microscopy and machine learning-assisted segmentation challenge the traditional model of proximal tubule endocytosis and instead support a model in which a continuous network of dense apical tubules, together with the endoplasmic reticulum, regulates the control of ligand passage, fission and dissociation. In addition to its function as an endocytic receptor, megalin maintains proximal tubule function through other mechanisms. Genomic analyses and animal studies show that predicted alterations in megalin expression have complex effects on disease progression and protection. Consistent with these observations, megalin expression affects proximal tubule transcription and cell metabolism, with important consequences for disease pathology.