Proximal tubule transferrin uptake is modulated by cellular iron and mediated by apical membrane megalin–cubilin complex and transferrin receptor 1

Craig P. Smith, Wing-kee Lee, Matthew Haley, Søren B. Poulsen, Frank Thévenod, Robert A. Fenton

Research output: Contribution to journalArticlepeer-review

Abstract

Receptor-mediated endocytosis is responsible for reabsorption of transferrin (Tf) in renal proximal tubules (PTs). Although the role of the megalin–cubilin receptor complex (MCRC) in this process is unequivocal, modalities independent of this complex are evident, but as yet undefined. Here, using immunostaining and Tf-flux assays, FACS analysis, and fluorescence imaging, we report localization of Tf receptor 1 (TfR1), the cognate Tf receptor mediating cellular holo-Tf (hTf) acquisition, to the apical brush border of the PT, with expression gradually declining along the PT in mouse and rat kidneys. In functional studies, hTf uptake across the apical membrane of cultured PT epithelial cell (PTEC) monolayers increased in response to decreased cellular iron after desferrioxamine (DFO) treatment. We also found that apical hTf uptake under basal conditions is receptor-associated protein (RAP)-sensitive and therefore mediated by the MCRC, but becomes RAP-insensitive under DFO treatment, with concomitantly decreased megalin and cubilin expression levels and increased TfR1 expression. Thus, as well as the MCRC, TfR1 mediates hTf uptake across the PT apical brush border, but in conditions of decreased cellular iron, hTf uptake is predominated by augmented apical TfR1. In conclusion, both the MCRC and TfR1 mediate hTf uptake across apical brush border membranes of PTECs and reciprocally respond to decreased cellular iron. Our findings have implications for renal health, whole-body iron homeostasis, and pathologies arising from disrupted iron balance.
Original languageEnglish
Pages (from-to)7025-7036
Number of pages12
JournalJournal of Biological Chemistry
Volume294
Issue number17
Early online date4 Mar 2019
DOIs
Publication statusPublished - 26 Apr 2019

Keywords

  • chelation
  • cubilin
  • endocytosis
  • epithelial cell
  • iron
  • kidney
  • megalin
  • membrane transport
  • renal physiology
  • transferrin
  • transferrin receptor

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