An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.
Steroid hormones may enter cells by diffusion through the plasma membrane. However, we demonstrate here that some steroid hormones are taken up by receptor-mediated endocytosis of steroid-carrier complexes. We show that 25-(OH) vitamin D3 in complex with its plasma carrier, the vitamin D-binding protein, is filtered through the glomerulus and reabsorbed in the proximal tubules by the endocytic receptor megalin. Endocytosis is required to preserve 25-(OH) vitamin D3 and to deliver to the cells the precursor for generation of 1,25-(OH)2 vitamin D3, a regulator of the calcium metabolism. Megalin-/- mice are unable to retrieve the steroid from the glomerular filtrate and develop vitamin D deficiency and bone disease.
Nykjaer
A
A
Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
Dragun
D
D
Walther
D
D
Vorum
H
H
Jacobsen
C
C
Herz
J
J
Melsen
F
F
Christensen
E I
EI
Willnow
T E
TE
D000818:Animals; D001846:Bone Development / Q000235:genetics; D053493:Cholestanetriol 26-Monooxygenase; D004705:Endocytosis / Q000502:physiology*; D026541:Heymann Nephritis Antigenic Complex; D006801:Humans; D007457:Iodine Radioisotopes; D007687:Kidney Tubules, Proximal / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000493:pharmacokinetics*; D014807:Vitamin D / Q000378:metabolism*; D014808:Vitamin D Deficiency / Q000235:genetics / Q000378:metabolism; D014809:Vitamin D-Binding Protein / Q000652:urine
D026541:Heymann Nephritis Antigenic Complex; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D011973:Receptors, LDL; D014809:Vitamin D-Binding Protein; D014807:Vitamin D; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse