title: Semaphorin3a promotes advanced diabetic nephropathy.
abstract: The onset of diabetic nephropathy (DN) is highlighted by glomerular filtration barrier abnormalities. Identifying pathogenic factors and targetable pathways driving DN is crucial to developing novel therapies and improving the disease outcome. Semaphorin3a (sema3a) is a guidance protein secreted by podocytes. Excess sema3a disrupts the glomerular filtration barrier. Here, using immunohistochemistry, we show increased podocyte SEMA3A in renal biopsies from patients with advanced DN. Using inducible, podocyte-specific Sema3a gain-of-function (Sema3a(+)) mice made diabetic with streptozotocin, we demonstrate that sema3a is pathogenic in DN. Diabetic Sema3a(+) mice develop massive proteinuria, renal insufficiency, and extensive nodular glomerulosclerosis, mimicking advanced DN in humans. In diabetic mice, Sema3a(+) exacerbates laminin and collagen IV accumulation in Kimmelstiel-Wilson-like glomerular nodules and causes diffuse podocyte foot process effacement and F-actin collapse via nephrin, αvβ3 integrin, and MICAL1 interactions with plexinA1. MICAL1 knockdown and sema3a inhibition render podocytes not susceptible to sema3a-induced shape changes, indicating that MICAL1 mediates sema3a-induced podocyte F-actin collapse. Moreover, sema3a binding inhibition or podocyte-specific plexinA1 deletion markedly ameliorates albuminuria and abrogates renal insufficiency and the diabetic nodular glomerulosclerosis phenotype of diabetic Sema3a(+) mice. Collectively, these findings indicate that excess sema3a promotes severe diabetic nephropathy and identifies novel potential therapeutic targets for DN.
authors.affiliation: Department of Pediatrics/Nephrology, Yale University School of Medicine, New Haven, CT.
authors.forename: Pardeep K
authors.initials: PK
authors.lastname: Aggarwal
authors.affiliation: Department of Pediatrics/Nephrology, Yale University School of Medicine, New Haven, CT.
authors.forename: Delma
authors.initials: D
authors.lastname: Veron
authors.affiliation: Department of Pathology, University of Miami Miller School of Medicine, Miami, FL.
authors.forename: David B
authors.initials: DB
authors.lastname: Thomas
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA.
authors.forename: Dionicio
authors.initials: D
authors.lastname: Siegel
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT.
authors.forename: Gilbert
authors.initials: G
authors.lastname: Moeckel
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT.
authors.forename: Michael
authors.initials: M
authors.lastname: Kashgarian
authors.affiliation: Department of Pediatrics/Nephrology, Yale University School of Medicine, New Haven, CT alda.tufro@yale.edu.
authors.forename: Alda
authors.initials: A
authors.lastname: Tufro
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002867:Chromones; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D007797:Laminin / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D050199:Podocytes / Q000378:metabolism*; D011507:Proteinuria / Q000209:etiology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D051437:Renal Insufficiency; D040121:Semaphorin-3A / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism; D044004:Xanthones
chemical_list: D000199:Actins; D002867:Chromones; D024141:Collagen Type IV; D039302:Integrin alphaVbeta3; D007797:Laminin; D008565:Membrane Proteins; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C492114:Plxna1 protein, mouse; D011956:Receptors, Cell Surface; D040121:Semaphorin-3A; D025721:WT1 Proteins; D044004:Xanthones; C113267:nephrin; C477901:xanthofulvin; C507541:Mical1 protein, mouse; D006899:Mixed Function Oxygenases