Reevaluating the role of megalin in renal vitamin D homeostasis using a human cell-derived microphysiological system

ALTEX
Brian D ChapronKenneth E Thummel

Abstract

The role of megalin in the regulation of renal vitamin D homeostasis has previously been evaluated in megalin-knockout mice and rat proximal tubule epithelial cells. We revisited these hypotheses that were previously tested solely in rodent models, this time using a 3-dimensional proximal tubule microphysiological system incorporating primary human proximal tubule epithelial cells. Using this human cell-derived model, we confirmed that 25OHD3 is transported into the human proximal tubule epithelium via megalin-mediated endocytosis while bound to vitamin D binding protein. Building upon these findings, we then evaluated the role of megalin in modulating the cellular uptake and biological activity of 1α,25(OH)2D3. Inhibition of megalin function decreased the 1α,25(OH)2D3-mediated induction of both cytochrome P450 24A1 protein levels and 24-hydroxylation activity following perfusion with vitamin D binding protein and 1α,25(OH)2D3. The potential for reciprocal effects from 1α,25(OH)2D3 on megalin expression were also tested. Contrary to previously published observations from rat proximal tubule epithelial cells, 1α,25(OH)2D3 did not induce megalin gene expression, thus highlighting the potential for meaningful interspecies differen...Continue Reading

Citations

Mar 25, 2020·Metabolites·Guido GembilloDomenico Santoro
Aug 29, 2019·International Journal of Molecular Sciences·Klaudia BerkowskaEwa Marcinkowska
Jan 12, 2021·Clinical Nutrition : Official Journal of the European Society of Parenteral and Enteral Nutrition·Jinhua WuYunxian Yu
Mar 7, 2021·Medicina·Guido GembilloDomenico Santoro
Oct 10, 2020·The Journal of Steroid Biochemistry and Molecular Biology·Anja C BaurGabriele I Stangl

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