Semaphorin3a disrupts podocyte foot processes causing acute proteinuria.
Semaphorin3a was discovered as a secreted guidance protein that acts as a chemorepellent to migrating axons and endothelial cells. In the adult mouse kidney, it is expressed in podocytes and collecting tubules. Here, we show that exogenous semaphorin3a caused acute nephrotic range proteinuria associated with podocyte foot process effacement and fusion, endothelial cell damage, decreased vascular endothelial growth factor-A receptor expression, and downregulation of the slit-diaphragm proteins podocin, nephrin, and CD2-associated protein. When vascular endothelial growth factor 165 was administered at the same time as Semaphorin3a, no proteinuria or renal ultrastructural abnormalities occurred, suggesting that semaphorin3a effects may be mediated, in part, by downregulation of vascular endothelial growth factor receptor 2 signaling. Our findings indicate that a balance of semaphorin3a to vascular endothelial growth factor-A may be important for glomerular filtration barrier homeostasis.
Tapia
R
R
Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Guan
F
F
Gershin
I
I
Teichman
J
J
Villegas
G
G
Tufro
A
A
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology; D000818:Animals; D003598:Cytoskeletal Proteins / Q000276:immunology; D015536:Down-Regulation; D050533:Glomerular Basement Membrane / Q000187:drug effects / Q000473:pathology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D010539:Permeability; D050199:Podocytes / Q000187:drug effects / Q000473:pathology*; D011507:Proteinuria / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000633:toxicity; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D011994:Recombinant Proteins; D040121:Semaphorin-3A; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C113267:nephrin; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2