Tubular proteinuria in mice and humans lacking the intrinsic lysosomal protein SCARB2/Limp-2

M. J. Desmond, D. Lee, S. A. Fraser, M. Katerelos, K. Gleich, P. Martinello, Y. Q. Li, M. C. Thomas, R. Michelucci, A. J. Cole, P. Saftig, M. Schwake, D. Stapleton, S. F. Berkovic, D. A. Power

Research output: Contribution to journalArticle

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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 lowmolecular- 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/cubilindependent, 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.

Original languageEnglish
JournalAmerican Journal of Physiology - Renal Physiology
Volume300
Issue number6
DOIs
Publication statusPublished - Jun 2011

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Proteinuria
Low Density Lipoprotein Receptor-Related Protein-2
Endocytosis
Proteolysis
Class B Scavenger Receptors
Myoclonic Epilepsy
Kidney
Retinol-Binding Proteins
Cathepsin B
Proximal Kidney Tubule
Proteins
Endosomes
Sclerosis
Bovine Serum Albumin
Lysosomes
lysosomal proteins
Peptide Hydrolases
Weights and Measures

Keywords

  • Albuminuria
  • Lysosome

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Tubular proteinuria in mice and humans lacking the intrinsic lysosomal protein SCARB2/Limp-2. / Desmond, M. J.; Lee, D.; Fraser, S. A.; Katerelos, M.; Gleich, K.; Martinello, P.; Li, Y. Q.; Thomas, M. C.; Michelucci, R.; Cole, A. J.; Saftig, P.; Schwake, M.; Stapleton, D.; Berkovic, S. F.; Power, D. A.

In: American Journal of Physiology - Renal Physiology, Vol. 300, No. 6, 06.2011.

Research output: Contribution to journalArticle

Desmond, MJ, Lee, D, Fraser, SA, Katerelos, M, Gleich, K, Martinello, P, Li, YQ, Thomas, MC, Michelucci, R, Cole, AJ, Saftig, P, Schwake, M, Stapleton, D, Berkovic, SF & Power, DA 2011, 'Tubular proteinuria in mice and humans lacking the intrinsic lysosomal protein SCARB2/Limp-2', American Journal of Physiology - Renal Physiology, vol. 300, no. 6. https://doi.org/10.1152/ajprenal.00015.2011
Desmond, M. J. ; Lee, D. ; Fraser, S. A. ; Katerelos, M. ; Gleich, K. ; Martinello, P. ; Li, Y. Q. ; Thomas, M. C. ; Michelucci, R. ; Cole, A. J. ; Saftig, P. ; Schwake, M. ; Stapleton, D. ; Berkovic, S. F. ; Power, D. A. / Tubular proteinuria in mice and humans lacking the intrinsic lysosomal protein SCARB2/Limp-2. In: American Journal of Physiology - Renal Physiology. 2011 ; Vol. 300, No. 6.
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AU - Gleich, K.

AU - Martinello, P.

AU - Li, Y. Q.

AU - Thomas, M. C.

AU - Michelucci, R.

AU - Cole, A. J.

AU - Saftig, P.

AU - Schwake, M.

AU - Stapleton, D.

AU - Berkovic, S. F.

AU - Power, D. A.

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