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

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DOI

  • Craig P Smith, From the School of Medical Sciences, The University of Manchester, Manchester M13 9PT, United Kingdom, craig.smith@manchester.ac.uk.
  • ,
  • Wing-Kee Lee, Physiology, Pathophysiology and Toxicology, University of Witten/Herdecke, D-58453 Witten, Germany, and.
  • ,
  • Matthew Haley, From the School of Medical Sciences, The University of Manchester, Manchester M13 9PT, United Kingdom.
  • ,
  • Søren B Poulsen
  • Frank Thévenod, Physiology, Pathophysiology and Toxicology, University of Witten/Herdecke, D-58453 Witten, Germany, and.
  • ,
  • Robert A Fenton

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.

OriginalsprogEngelsk
TidsskriftThe Journal of biological chemistry
Vol/bind294
Nummer17
Sider (fra-til)7025-7036
Antal sider12
ISSN0021-9258
DOI
StatusUdgivet - 26 apr. 2019
Eksternt udgivetJa

Bibliografisk note

© 2019 Smith et al.

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