Abstract

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

Highlights

  • In humans, conversion of 25-hydroxyvitamin D3 (25OHD3) to its bioactive form, 1α,25(OH)2D3, occurs primarily in the renal proximal tubule

  • 3.2 D binding protein (DBP) and fetal bovine serum (FBS) differentially affect the regulation of cytochrome P450 24A1 (CYP24A1) activity by 1α,25(OH)2D3 DBP is considered essential for megalin-mediated uptake of 25OHD3 (Nykjaer et al, 1999)

  • We observed several key findings: (1) megalin plays a critical role in the delivery of DBP-bound 25OHD3 to the human proximal tubule, (2) megalin-mediated endocytosis of DBP-bound 1α,25(OH)2D3 is essential to achieve the maximal physiological response, and (3) elevated 1α,25(OH)2D3 levels do not induce, and may even suppress, megalin gene expression in human proximal tubule epithelial cells (PTECs), contrasting with previously published observations of induction in immortalized rat PTECs (Liu et al, 1998)

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Summary

Introduction

Conversion of 25OHD3 to its bioactive form, 1α,25(OH)2D3, occurs primarily in the renal proximal tubule It is a tightly regulated process, controlled by a number of intracrine and endocrine feedback loops (Wang et al, 2015; Dusso et al, 2005; Maiti and Beckman, 2007; Perwad et al, 2007). In order for the proximal tubule epithelial cells (PTECs) to sense and respond to systemic demands for more or less 1α,25(OH)2D3, both 1α,25(OH)2D3 and its metabolic precursor, 25OHD3, must gain intracellular access. Both 1α,25(OH)2D3 and 25OHD3 circulate tightly bound to vitamin D binding protein (DBP) (Bikle et al, 1985, 1986). Passive permeability of the unbound hormone and prohormone alone would yield low unbound intracellular concentrations (Dusso et al, 2005). Nykjaer et al (1999) conducted a series of experiments in megalin-knockout mice and reported that the major route by which 25OHD3 accesses murine PTECs is via megalin-mediated endocytosis of the DBP-bound

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