Semaphorin3a regulates endothelial cell number and podocyte differentiation during glomerular development.
Semaphorin3a (Sema3a), a chemorepellant guidance protein, plays crucial roles in neural, cardiac and peripheral vascular patterning. Sema3a is expressed in the developing nephron, mature podocytes and collecting tubules. Sema3a acts as a negative regulator of ureteric bud branching, but its function in glomerular development has not been examined. Here we tested the hypothesis that Sema3a regulates glomerular vascular development using loss- and gain-of-function mouse models. Sema3a deletion resulted in defects in renal vascular patterning, excess endothelial cells within glomerular capillaries, effaced podocytes with extremely wide foot processes and albuminuria. Podocyte Sema3a overexpression during organogenesis resulted in glomerular hypoplasia, characterized by glomerular endothelial cell apoptosis, delayed and abnormal podocyte foot process development, a complete absence of slit diaphragms and congenital proteinuria. Nephrin, WT1 and VEGFR2 were downregulated in Sema3a-overexpressing kidneys. We conclude that Sema3a is an essential negative regulator of endothelial cell survival in developing glomeruli and plays a crucial role in podocyte differentiation in vivo. Hence, a tight regulation of Sema3a dosage is required for the establishment of a normal glomerular filtration barrier.
Reidy
Kimberly J
KJ
Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA.
Villegas
Guillermo
G
Teichman
Jason
J
Veron
Delma
D
Shen
Wa
W
Jimenez
Juan
J
Thomas
David
D
Tufro
Alda
A
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D019085:Fluorescent Antibody Technique, Direct; D005456:Fluorescent Dyes / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D031295:Griffonia / Q000737:chemistry; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000378:metabolism; D007678:Kidney Glomerulus / Q000254:growth & development* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D037121:Plant Lectins / Q000378:metabolism; D050199:Podocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D040121:Semaphorin-3A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D005456:Fluorescent Dyes; D007211:Indoles; D037121:Plant Lectins; D011994:Recombinant Proteins; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; C007293:DAPI