{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T07:44:45Z","timestamp":1790840685436,"version":"4.1.0"},"reference-count":52,"publisher":"American Diabetes Association","issue":"5","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,5,1]]},"abstract":"<jats:p>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, \u03b1v\u03b23 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.<\/jats:p>","DOI":"10.2337\/db14-0719","type":"journal-article","created":{"date-parts":[[2014,12,5]],"date-time":"2014-12-05T00:21:59Z","timestamp":1417738919000},"page":"1743-1759","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":62,"title":["Semaphorin3a Promotes Advanced Diabetic Nephropathy"],"prefix":"10.2337","volume":"64","author":[{"given":"Pardeep K.","family":"Aggarwal","sequence":"first","affiliation":[{"name":"Department of Pediatrics\/Nephrology, Yale University School of Medicine, New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delma","family":"Veron","sequence":"additional","affiliation":[{"name":"Department of Pediatrics\/Nephrology, Yale University School of Medicine, New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Miami Miller School of Medicine, Miami, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dionicio","family":"Siegel","sequence":"additional","affiliation":[{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilbert","family":"Moeckel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University School of Medicine, New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kashgarian","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University School of Medicine, New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alda","family":"Tufro","sequence":"additional","affiliation":[{"name":"Department of Pediatrics\/Nephrology, Yale University School of Medicine, New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2014,12,4]]},"reference":[{"key":"2022031303273935000_B1","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/nrendo.2013.184","article-title":"Diabetic nephropathy: diagnosis and treatment","volume":"9","author":"Fineberg","year":"2013","journal-title":"Nat Rev Endocrinol"},{"key":"2022031303273935000_B2","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1152\/physrev.00045.2011","article-title":"Mechanisms of diabetic complications","volume":"93","author":"Forbes","year":"2013","journal-title":"Physiol Rev"},{"key":"2022031303273935000_B3","doi-asserted-by":"crossref","first-page":"S63","DOI":"10.1053\/j.ajkd.2013.10.047","article-title":"New insights into molecular mechanisms of diabetic kidney disease","volume":"63","author":"Badal","year":"2014","journal-title":"Am J Kidney Dis"},{"key":"2022031303273935000_B4","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.semnephrol.2012.07.007","article-title":"Drug discovery for diabetic nephropathy: trying the leap from mouse to man","volume":"32","author":"Breyer","year":"2012","journal-title":"Semin Nephrol"},{"key":"2022031303273935000_B5","doi-asserted-by":"crossref","first-page":"64","DOI":"10.2337\/diab.32.2.S64","article-title":"The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy","volume":"32","author":"Mogensen","year":"1983","journal-title":"Diabetes"},{"key":"2022031303273935000_B6","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.semnephrol.2012.06.010","article-title":"VEGF and podocytes in diabetic nephropathy","volume":"32","author":"Tufro","year":"2012","journal-title":"Semin Nephrol"},{"key":"2022031303273935000_B7","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1093\/ndt\/gfs121","article-title":"Cellular and molecular mechanisms of diabetic glomerulopathy","volume":"27","author":"Gnudi","year":"2012","journal-title":"Nephrol Dial Transplant"},{"key":"2022031303273935000_B8","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1681\/ASN.2012121218","article-title":"Targeted glomerular angiopoietin-1 therapy for early diabetic kidney disease","volume":"25","author":"Dessapt-Baradez","year":"2014","journal-title":"J Am Soc Nephrol"},{"key":"2022031303273935000_B9","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.1007\/s00125-011-2270-x","article-title":"Deletion of platelet-derived growth factor receptor-\u03b2 improves diabetic nephropathy in Ca\u00b2\u207a\/calmodulin-dependent protein kinase II\u03b1 (Thr286Asp) transgenic mice","volume":"54","author":"Suzuki","year":"2011","journal-title":"Diabetologia"},{"key":"2022031303273935000_B10","doi-asserted-by":"crossref","first-page":"3093","DOI":"10.1681\/ASN.2006010064","article-title":"Blockade of vascular endothelial growth factor signaling ameliorates diabetic albuminuria in mice","volume":"17","author":"Sung","year":"2006","journal-title":"J Am Soc Nephrol"},{"key":"2022031303273935000_B11","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.2337\/db09-0119","article-title":"Abnormal angiogenesis in diabetic nephropathy","volume":"58","author":"Nakagawa","year":"2009","journal-title":"Diabetes"},{"key":"2022031303273935000_B12","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1146\/annurev.cellbio.22.010605.093554","article-title":"Semaphorin regulation of cellular morphology","volume":"23","author":"Tran","year":"2007","journal-title":"Annu Rev Cell Dev Biol"},{"key":"2022031303273935000_B13","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1002\/cm.20527","article-title":"Extracellular inhibitors, repellents, and semaphorin\/plexin\/MICAL-mediated actin filament disassembly","volume":"68","author":"Hung","year":"2011","journal-title":"Cytoskeleton (Hoboken)"},{"key":"2022031303273935000_B14","doi-asserted-by":"crossref","first-page":"S149","DOI":"10.1016\/S0925-4773(03)00108-4","article-title":"Ontogeny of semaphorins 3A and 3F and their receptors neuropilins 1 and 2 in the kidney","volume":"119","author":"Villegas","year":"2002","journal-title":"Mech Dev"},{"key":"2022031303273935000_B15","doi-asserted-by":"crossref","first-page":"3979","DOI":"10.1242\/dev.037267","article-title":"Semaphorin3a regulates endothelial cell number and podocyte differentiation during glomerular development","volume":"136","author":"Reidy","year":"2009","journal-title":"Development"},{"key":"2022031303273935000_B16","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1016\/j.ajpath.2013.06.022","article-title":"Excess podocyte semaphorin-3A leads to glomerular disease involving plexinA1-nephrin interaction","volume":"183","author":"Reidy","year":"2013","journal-title":"Am J Pathol"},{"key":"2022031303273935000_B17","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/S0092-8674(00)80535-8","article-title":"Neuropilin is a semaphorin III receptor","volume":"90","author":"Kolodkin","year":"1997","journal-title":"Cell"},{"key":"2022031303273935000_B18","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S0092-8674(00)80062-8","article-title":"Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors","volume":"99","author":"Takahashi","year":"1999","journal-title":"Cell"},{"key":"2022031303273935000_B19","first-page":"233","article-title":"Neuropilin-1 mediates collapsin-1\/semaphorin III inhibition of endothelial cell motility: functional competition of collapsin-1 and vascular endothelial growth factor-165","volume":"146","author":"Miao","year":"1999","journal-title":"J Cell Biol"},{"key":"2022031303273935000_B20","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/S0092-8674(02)00794-8","article-title":"MICALs, a family of conserved flavoprotein oxidoreductases, function in plexin-mediated axonal repulsion","volume":"109","author":"Terman","year":"2002","journal-title":"Cell"},{"key":"2022031303273935000_B21","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nature08724","article-title":"Mical links semaphorins to F-actin disassembly","volume":"463","author":"Hung","year":"2010","journal-title":"Nature"},{"key":"2022031303273935000_B22","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1126\/science.1211956","article-title":"Direct redox regulation of F-actin assembly and disassembly by Mical","volume":"334","author":"Hung","year":"2011","journal-title":"Science"},{"key":"2022031303273935000_B23","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1038\/ncb2871","article-title":"SelR reverses Mical-mediated oxidation of actin to regulate F-actin dynamics","volume":"15","author":"Hung","year":"2013","journal-title":"Nat Cell Biol"},{"key":"2022031303273935000_B24","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1007\/s00125-010-2034-z","article-title":"Podocyte vascular endothelial growth factor (Vegf164) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes","volume":"54","author":"Veron","year":"2011","journal-title":"Diabetologia"},{"key":"2022031303273935000_B25","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/nm1570","article-title":"Sema3a maintains normal heart rhythm through sympathetic innervation patterning","volume":"13","author":"Ieda","year":"2007","journal-title":"Nat Med"},{"key":"2022031303273935000_B26","doi-asserted-by":"crossref","first-page":"10482","DOI":"10.1073\/pnas.152238499","article-title":"Early restriction of peripheral and proximal cell lineages during formation of the lung","volume":"99","author":"Perl","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031303273935000_B27","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/ncb1416","article-title":"Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis","volume":"8","author":"Takegahara","year":"2006","journal-title":"Nat Cell Biol"},{"key":"2022031303273935000_B28","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1681\/ASN.2013070752","article-title":"Podocyte-specific VEGF-a gain of function induces nodular glomerulosclerosis in eNOS null mice","volume":"25","author":"Veron","year":"2014","journal-title":"J Am Soc Nephrol"},{"key":"2022031303273935000_B29","doi-asserted-by":"crossref","first-page":"3603","DOI":"10.1128\/MCB.01389-10","article-title":"MICAL-1 is a negative regulator of MST-NDR kinase signaling and apoptosis","volume":"31","author":"Zhou","year":"2011","journal-title":"Mol Cell Biol"},{"key":"2022031303273935000_B30","doi-asserted-by":"crossref","first-page":"610","DOI":"10.7164\/antibiotics.56.610","article-title":"Xanthofulvin, a novel semaphorin inhibitor produced by a strain of Penicillium","volume":"56","author":"Kumagai","year":"2003","journal-title":"J Antibiot (Tokyo)"},{"key":"2022031303273935000_B31","doi-asserted-by":"crossref","first-page":"3421","DOI":"10.1002\/anie.201205837","article-title":"Syntheses of xanthofulvin and vinaxanthone, natural products enabling spinal cord regeneration","volume":"52","author":"Axelrod","year":"2013","journal-title":"Angew Chem Int Ed Engl"},{"key":"2022031303273935000_B32","doi-asserted-by":"crossref","first-page":"R146","DOI":"10.1186\/ar3881","article-title":"Semaphorin 3A is a marker for disease activity and a potential immunoregulator in systemic lupus erythematosus","volume":"14","author":"Vadasz","year":"2012","journal-title":"Arthritis Res Ther"},{"key":"2022031303273935000_B33","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1681\/ASN.2010010010","article-title":"Pathologic classification of diabetic nephropathy","volume":"21","author":"Tervaert","year":"2010","journal-title":"J Am Soc Nephrol"},{"key":"2022031303273935000_B34","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s007950070004","article-title":"Ultrastructural characteristics of diabetic nephropathy","volume":"33","author":"Nishi","year":"2000","journal-title":"Med Electron Microsc"},{"key":"2022031303273935000_B35","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.1681\/ASN.2006070798","article-title":"Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice","volume":"17","author":"Zhao","year":"2006","journal-title":"J Am Soc Nephrol"},{"key":"2022031303273935000_B36","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1681\/ASN.2006050459","article-title":"Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy","volume":"18","author":"Nakagawa","year":"2007","journal-title":"J Am Soc Nephrol"},{"key":"2022031303273935000_B37","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1681\/ASN.2006121358","article-title":"Overexpression of calmodulin in pancreatic beta cells induces diabetic nephropathy","volume":"19","author":"Yuzawa","year":"2008","journal-title":"J Am Soc Nephrol"},{"key":"2022031303273935000_B38","doi-asserted-by":"crossref","first-page":"3248","DOI":"10.2337\/diabetes.53.12.3248","article-title":"Development of late-stage diabetic nephropathy in OVE26 diabetic mice","volume":"53","author":"Zheng","year":"2004","journal-title":"Diabetes"},{"key":"2022031303273935000_B39","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1681\/ASN.2009121290","article-title":"BTBR Ob\/Ob mutant mice model progressive diabetic nephropathy","volume":"21","author":"Hudkins","year":"2010","journal-title":"J Am Soc Nephrol"},{"key":"2022031303273935000_B40","doi-asserted-by":"crossref","first-page":"2503","DOI":"10.1681\/ASN.2009070721","article-title":"Mouse models of diabetic nephropathy","volume":"20","author":"Brosius","year":"2009","journal-title":"J Am Soc Nephrol"},{"key":"2022031303273935000_B41","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.2215\/CJN.02510213","article-title":"The modern spectrum of renal biopsy findings in patients with diabetes","volume":"8","author":"Sharma","year":"2013","journal-title":"Clin J Am Soc Nephrol"},{"key":"2022031303273935000_B42","doi-asserted-by":"crossref","first-page":"10190","DOI":"10.1073\/pnas.1005144107","article-title":"Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice","volume":"107","author":"Kakoki","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031303273935000_B43","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.jdiacomp.2007.11.011","article-title":"Association of endothelial nitric oxide synthase Glu298Asp, 4b\/a, and -786T&gt;C gene variants with diabetic nephropathy","volume":"22","author":"Ezzidi","year":"2008","journal-title":"J Diabetes Complications"},{"key":"2022031303273935000_B44","doi-asserted-by":"crossref","first-page":"S56","DOI":"10.1046\/j.1523-1755.2000.07504.x","article-title":"Elevated vascular endothelial growth factor in type 1 diabetic patients with diabetic nephropathy","volume":"75","author":"Hovind","year":"2000","journal-title":"Kidney Int Suppl"},{"key":"2022031303273935000_B45","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/nature01784","article-title":"Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function","volume":"424","author":"Serini","year":"2003","journal-title":"Nature"},{"key":"2022031303273935000_B46","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1038\/sj.ki.5000313","article-title":"Autocrine class 3 semaphorin system regulates slit diaphragm proteins and podocyte survival","volume":"69","author":"Guan","year":"2006","journal-title":"Kidney Int"},{"key":"2022031303273935000_B47","doi-asserted-by":"crossref","first-page":"2287","DOI":"10.1523\/JNEUROSCI.5646-07.2008","article-title":"Release of MICAL autoinhibition by semaphorin-plexin signaling promotes interaction with collapsin response mediator protein","volume":"28","author":"Schmidt","year":"2008","journal-title":"J Neurosci"},{"key":"2022031303273935000_B48","doi-asserted-by":"crossref","first-page":"42985","DOI":"10.1074\/jbc.M302395200","article-title":"In vitro and in vivo characterization of a novel semaphorin 3A inhibitor, SM-216289 or xanthofulvin","volume":"278","author":"Kikuchi","year":"2003","journal-title":"J Biol Chem"},{"key":"2022031303273935000_B49","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.molcel.2013.06.019","article-title":"MsrB1 and MICALs regulate actin assembly and macrophage function via reversible stereoselective methionine oxidation","volume":"51","author":"Lee","year":"2013","journal-title":"Mol Cell"},{"key":"2022031303273935000_B50","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1038\/nm1505","article-title":"A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord","volume":"12","author":"Kaneko","year":"2006","journal-title":"Nat Med"},{"key":"2022031303273935000_B51","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/nature11000","article-title":"Osteoprotection by semaphorin 3A","volume":"485","author":"Hayashi","year":"2012","journal-title":"Nature"},{"key":"2022031303273935000_B52","doi-asserted-by":"crossref","first-page":"e58446","DOI":"10.1371\/journal.pone.0058446","article-title":"Semaphorin 3A is a new early diagnostic biomarker of experimental and pediatric acute kidney injury","volume":"8","author":"Jayakumar","year":"2013","journal-title":"PLoS One"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/64\/5\/1743\/579634\/db140719.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/64\/5\/1743\/579634\/db140719.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T12:42:26Z","timestamp":1717591346000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/64\/5\/1743\/40533\/Semaphorin3a-Promotes-Advanced-Diabetic"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12,4]]},"references-count":52,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2014,12,4]]},"published-print":{"date-parts":[[2015,5,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db14-0719","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.725264790.793503867","asserted-by":"object"}]},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,12,4]]}}}