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Animal Model |
From the Max-Delbrueck-Center for Molecular Medicine,*
Berlin, and Childrens Hospital,
Ludwig-Maximilians-University, Munich, Germany; the Departments of
Medical Biochemistry
and Cell
Biology,||
University of Aarhus, Aarhus, Denmark; INSERM
U25, §
Necker Hospital, Paris, France; and the
Institute for Nutritional Research,¶
University of
Oslo, Oslo, Norway
Megalin is an endocytic receptor expressed on the luminal surface
of the renal proximal tubules. The receptor is believed to play an
important role in the tubular uptake of macromolecules filtered through
the glomerulus. To elucidate the role of megalin in vivo
and to identify its endogenous ligands, we analyzed the
proximal tubular function in mice genetically deficient for the
receptor. We demonstrate that megalin-deficient mice exhibit a tubular
resorption deficiency and excrete low molecular weight plasma proteins
in the urine (low molecular weight proteinuria). Proteins excreted
include small plasma proteins that carry lipophilic compounds including
vitamin D-binding protein, retinol-binding protein,
1-microglobulin and odorant-binding protein. Megalin
binds these proteins and mediates their cellular uptake. Urinary loss
of carrier proteins in megalin-deficient mice results in concomitant
loss of lipophilic vitamins bound to the carriers. Similar to megalin
knockout mice, patients with low molecular weight proteinuria
as in Fanconi syndrome are also shown to excrete vitamin/carrier
complexes. Thus, these results identify a crucial role of the
proximal tubule in retrieval of filtered vitamin/carrier complexes and
the central role played by megalin in this process.
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