The soluble intracellular domain of megalin does not affect renal proximal tubular function in vivo.
Megalin-mediated endocytic uptake constitutes the main pathway for clearance of plasma proteins from the glomerular filtrate in proximal tubules. Little is known, however, about mechanisms that control megalin expression and activity in the kidney. A widely discussed hypothesis states that upon ligand binding a regulated intramembrane proteolysis releases the cytosolic domain of megalin and this fragment subsequently modulates megalin gene transcription. Here, we tested this by generating a mouse model that co-expressed both the soluble intracellular domain and full-length megalin. Despite pronounced synthesis in the proximal tubules, the soluble intracellular domain failed to exert distinct effects on renal proximal tubular function, including megalin expression, endocytic retrieval of proteins, or global renal gene transcription. Hence, our study argues that the soluble intracellular domain does not have a role in regulating the activity of megalin in the kidney.
Christ
Annabel
A
Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, Berlin, Germany.
Terryn
Sara
S
Schmidt
Vanessa
V
Christensen
Erik I
EI
Huska
Matthew R
MR
Andrade-Navarro
Miguel A
MA
Hübner
Norbert
N
Devuyst
Olivier
O
Hammes
Annette
A
Willnow
Thomas E
TE
D000818:Animals; D007687:Kidney Tubules, Proximal / Q000502:physiology*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D017434:Protein Structure, Tertiary
D026561:Low Density Lipoprotein Receptor-Related Protein-2; C055127:Lrp2 protein, mouse