title: Tubular proteinuria in mice and humans lacking the intrinsic lysosomal protein SCARB2/Limp-2.
abstract: Deficiency of the intrinsic lysosomal protein human scavenger receptor class B, member 2 (SCARB2; Limp-2 in mice) causes collapsing focal and segmental glomerular sclerosis (FSGS) and myoclonic epilepsy in humans, but patients with no apparent kidney damage have recently been described. We now demonstrate that these patients can develop tubular proteinuria. To determine the mechanism, mice deficient in Limp-2, the murine homolog of SCARB2, were studied. Most low-molecular-weight proteins filtered by the glomerulus are removed in the proximal convoluted tubule (PCT) by megalin/cubilin-dependent receptor-mediated endocytosis. Expression of megalin and cubilin was unchanged in Limp-2(-/-) mice, however, and the initial uptake of injected Alexa Fluor 555-conjugated bovine serum albumin (Alexa-BSA) was similar to wild-type mice, indicating that megalin/cubilin-dependent, receptor-mediated endocytosis was unaffected. There was a defect in proteolysis of reabsorbed proteins in the Limp-2(-/-) mice, demonstrated by the persistence of Alexa-BSA in the PCT compared with controls. This was associated with the failure of the lysosomal protease cathepsin B to colocalize with Alexa-BSA and endogenous retinol-binding protein in kidneys from Limp-2(-/-) mice. The data suggest that tubular proteinuria in Limp-2(-/-) mice is due to failure of endosomes containing reabsorbed proteins to fuse with lysosomes in the proximal tubule of the kidney. Failure of proteolysis is a novel mechanism for tubular proteinuria.
authors.affiliation: Department of Nephrology, Baker IDI Heart and Diabetes Institute, Victoria, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: Desmond
authors.forename: D
authors.initials: D
authors.lastname: Lee
authors.forename: S A
authors.initials: SA
authors.lastname: Fraser
authors.forename: M
authors.initials: M
authors.lastname: Katerelos
authors.forename: K
authors.initials: K
authors.lastname: Gleich
authors.forename: P
authors.initials: P
authors.lastname: Martinello
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Li
authors.forename: M C
authors.initials: MC
authors.lastname: Thomas
authors.forename: R
authors.initials: R
authors.lastname: Michelucci
authors.forename: A J
authors.initials: AJ
authors.lastname: Cole
authors.forename: P
authors.initials: P
authors.lastname: Saftig
authors.forename: M
authors.initials: M
authors.lastname: Schwake
authors.forename: D
authors.initials: D
authors.lastname: Stapleton
authors.forename: S F
authors.initials: SF
authors.lastname: Berkovic
authors.forename: D A
authors.initials: DA
authors.lastname: Power
mesh_terms: D000818:Animals; D005455:Fluorescent Antibody Technique; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000235:genetics* / Q000378:metabolism; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D011507:Proteinuria / Q000235:genetics* / Q000378:metabolism; D051116:Receptors, Scavenger / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; D051907:Lysosomal Membrane Proteins; D051116:Receptors, Scavenger; C074299:SCARB2 protein, human