title: Excess podocyte semaphorin-3A leads to glomerular disease involving plexinA1-nephrin interaction.
abstract: Semaphorin-3A (Sema3a), a guidance protein secreted by podocytes, is essential for normal kidney patterning and glomerular filtration barrier development. Here, we report that podocyte-specific Sema3a gain-of-function in adult mice leads to proteinuric glomerular disease involving the three layers of the glomerular filtration barrier. Reversibility of the glomerular phenotype upon removal of the transgene induction provided proof-of-principle of the cause-and-effect relationship between podocyte Sema3a excess and glomerular disease. Mechanistically, excess Sema3a induces dysregulation of nephrin, matrix metalloproteinase 9, and αvβ3 integrin in vivo. Sema3a cell-autonomously disrupts podocyte shape. We identified a novel direct interaction between the Sema3a signaling receptor plexinA1 and nephrin, linking extracellular Sema3a signals to the slit-diaphragm signaling complex. We conclude that Sema3a functions as an extracellular negative regulator of the structure and function of the glomerular filtration barrier in the adult kidney. Our findings demonstrate a crosstalk between Sema3a and nephrin signaling pathways that is functionally relevant both in vivo and in vitro.
authors: Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York.
authors: Kimberly J
authors: KJ
authors: Reidy
authors: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
authors: Pardeep K
authors: PK
authors: Aggarwal
authors: Imaging Facility, Albert Einstein College of Medicine, Bronx, New York.
authors: Juan J
authors: JJ
authors: Jimenez
authors: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York.
authors: David B
authors: DB
authors: Thomas
authors: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut.
authors: Delma
authors: D
authors: Veron
authors: Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut. Electronic address: alda.tufro@yale.edu.
authors: Alda
authors: A
authors: Tufro
mesh_terms: D000818:Animals; D048430:Cell Shape; D015536:Down-Regulation; D050533:Glomerular Basement Membrane / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology*; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D011485:Protein Binding; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D040121:Semaphorin-3A / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D039302:Integrin alphaVbeta3; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C492114:Plxna1 protein, mouse; D011956:Receptors, Cell Surface; D040121:Semaphorin-3A; C113267:nephrin
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