Up-regulation of the homophilic adhesion molecule sidekick-1 in podocytes contributes to glomerulosclerosis.
Focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease worldwide. Although the mechanisms underlying this important disease are poorly understood, the glomerular podocyte clearly plays a central role in disease pathogenesis. In the current work, we demonstrate that the homophilic adhesion molecule sidekick-1 (sdk-1) is up-regulated in podocytes in FSGS both in rodent models and in human kidney biopsy samples. Transgenic mice that have podocyte-specific overexpression of sdk-1 develop gradually progressive heavy proteinuria and severe FSGS. We also show that sdk-1 associates with the slit diaphragm linker protein MAGI-1, which is already known to interact with several critical podocyte proteins including synaptopodin, alpha-actinin-4, nephrin, JAM4, and beta-catenin. This interaction is mediated through a direct interaction between the carboxyl terminus of sdk-1 and specific PDZ domains of MAGI-1. In vitro expression of sdk-1 enables a dramatic recruitment of MAGI-1 to the cell membrane. Furthermore, a truncated version of sdk-1 that is unable to bind to MAGI-1 does not induce podocyte dysfunction when overexpressed. We conclude that the up-regulation of sdk-1 in podocytes is an important pathogenic factor in FSGS and that the mechanism involves disruption of the actin cytoskeleton possibly via alterations in MAGI-1 function.
Kaufman
Lewis
L
Division of Nephrology, Mount Sinai School of Medicine, New York, New York 10029, USA. kaufman@mssm.edu
Potla
Uma
U
Coleman
Sarah
S
Dikiy
Stanislav
S
Hata
Yutaka
Y
Kurihara
Hidetake
H
He
John C
JC
D'Agati
Vivette D
VD
Klotman
Paul E
PE
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D051528:Guanylate Kinases; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D050199:Podocytes / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011485:Protein Binding
D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D015816:Cell Adhesion Molecules, Neuronal; D007074:Immunoglobulin G; D008565:Membrane Proteins; C493091:SDK1 protein, human; C493090:sidekick-1 protein, mouse; D051528:Guanylate Kinases; C113338:MAGI1 protein, human; C493280:Magi1 protein, mouse