Protein reabsorption in renal proximal tubule-function and dysfunction in kidney pathophysiology.
The endocytic receptors megalin and cubilin are highly expressed in the early parts of the endocytic apparatus of the renal proximal tubule. The two receptors appear to be responsible for the tubular clearance of most proteins filtered in the glomeruli. Since cubilin is a peripheral membrane protein it has no endocytosis signaling sequence. Cubilin binds to megalin and it appears that megalin is responsible for internalization of cubilin and its ligands, in addition to internalizing its own ligands. The importance of the receptors is underscored by the proteinuria observed in megalin-deficient mice, in dogs lacking functional cubilin, and in patients with distinct mutations of the cubilin gene. In this review we focus on the role of megalin- and cubilin-mediated endocytosis in renal pathophysiology. Association between disorders characterized by tubular proteinuria, such as megaloblastic anemia type-1, Dent disease, cystinosis, and Fabry disease and the dysfunction of proximal tubular endocytosis is discussed. The correlation between the high capacity of endocytosis in the proximal tubule and progressive renal disease in overload proteinuria is considered.
Christensen
Erik I
EI
Department of Cell Biology, Institute of Anatomy, University of Aarhus, 8000 Aarhus C, Denmark. eic@ana.au.dk
Gburek
Jakub
J
D000042:Absorption; D000818:Animals; D002648:Child; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000503:physiopathology*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000502:physiology; D015394:Molecular Structure; D011506:Proteins / Q000493:pharmacokinetics*; D011507:Proteinuria / Q000378:metabolism / Q000503:physiopathology; D011956:Receptors, Cell Surface / Q000502:physiology
D026561:Low Density Lipoprotein Receptor-Related Protein-2; D011506:Proteins; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor