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J Biol Chem, Vol. 274, Issue 9, 5620-5625, February 26, 1999
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From the Parathyroid hormone (PTH) is predominantly
cleared from the circulation by glomerular filtration and degradation
in the renal proximal tubules. Here, we demonstrate that megalin, a
multifunctional endocytic receptor in the proximal tubular epithelium,
mediates the uptake and degradation of PTH. Megalin was purified from
kidney membranes as the major PTH-binding protein and shown in BIAcore analysis to specifically bind full-length PTH and amino-terminal PTH
fragments (Kd 0.5 µM). Absence of the
receptor in megalin knockout mice resulted in 4-fold increased levels
of amino-terminal PTH fragments in the urine. In F9 cells expressing
both megalin and the PTH/PTH-related peptide receptor (PTH/PTHrP
receptor), uptake and lysosomal degradation of the hormone was mediated
through megalin. Blocking megalin-mediated clearance of PTH resulted in 3-fold increased stimulation of the PTH/PTHrP receptor. These data
provide evidence that megalin is involved in the renal catabolism of
PTH and potentially antagonizes PTH/PTHrP receptor activity in the
proximal tubular epithelium.
Franz-Volhard-Clinic, Cell Biology, University of Aarhus, 8000 Aarhus, Denmark
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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