{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T09:14:12Z","timestamp":1768900452389,"version":"3.49.0"},"reference-count":48,"publisher":"Portland Press Ltd.","issue":"24","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,12,1]]},"abstract":"<jats:p>Our established interleukin-13 (IL-13) overexpression rat model of minimal change-like nephropathy provided a platform to study the molecular signalling pathways in T-helper 2 (Th2) cytokine associated minimal change nephrotic syndrome (MCNS). We hypothesized that IL-13 may act directly on podocytes, causing podocyte foot process effacement and hence proteinuria in our rat model of minimal change-like nephropathy. The present study aimed firstly to delineate the glomerular \u2018gene signature\u2019 associated with IL-13-mediated dysregulation of podocyte-related proteins, and subsequently to investigate the role of the differentially regulated genes (DEGs) in IL-13-mediated podocyte injury. Glomerular transcriptional profile of IL-13-overexpressed rats showed characteristic features of podocyte injury with 87% of podocyte-related genes being significantly down-regulated. Gene expression of Vav1 was shown to be highly up-regulated in the glomeruli of IL-13-overexpressed rats and pathway analysis of the DEGs suggested a possible novel role of Vav1\u00a0in podocyte cytoskeleton remodelling. Immunofluorescence examination demonstrated glomerular expression of Vav1\u00a0in rats which co-localized with synaptopodin, confirming podocyte expression. However, positive staining for the phosphorylated form of Vav1 (p-Vav1) was only seen in IL-13-overexpressed rats. Moreover, in\u00a0vitro IL-13 stimulation of human podocytes resulted in phosphorylation of Vav1. This was associated with Rac1 activation and actin cytoskeleton rearrangement, which was abrogated in Vav1 knockdown podocytes. In conclusion, we have demonstrated the role of Vav1-Rac1 pathway characterized by phosphorylation of Vav1, activation of Rac1 and the subsequent actin cytoskeleton rearrangement in IL-13-induced podocyte injury, possibly explaining the podocyte foot process effacement seen in our IL-13 overexpression rat model.<\/jats:p>","DOI":"10.1042\/cs20160312","type":"journal-article","created":{"date-parts":[[2016,10,5]],"date-time":"2016-10-05T22:28:50Z","timestamp":1475706530000},"page":"2317-2327","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Novel role of Vav1-Rac1 pathway in actin cytoskeleton regulation in interleukin-13-induced minimal change-like nephropathy"],"prefix":"10.1042","volume":"130","author":[{"given":"Chang-Yien","family":"Chan","sequence":"first","affiliation":[{"name":"Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore"},{"name":"KTP-National University Children's Medical Institute, National University Hospital, Singapore 119260, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kar-Hui","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore"},{"name":"KTP-National University Children's Medical Institute, National University Hospital, Singapore 119260, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinmiao","family":"Chen","sequence":"additional","affiliation":[{"name":"Bioinformatics, Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinhua","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Microbiology, National University of Singapore, Singapore 117599, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caroline\u00a0Guat-Lay","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, National University of Singapore, Singapore 117599, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Puay-Hoon","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Singapore General Hospital, Singapore 169608, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanley\u00a0C.","family":"Jordan","sequence":"additional","affiliation":[{"name":"Cedars-Sinai Medical Center, Los Angeles, CA 90048, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henry\u00a0Yang","family":"He","sequence":"additional","affiliation":[{"name":"Cancer Science Institute, National University of Singapore, Singapore 119260, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui-Kim","family":"Yap","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore"},{"name":"KTP-National University Children's Medical Institute, National University Hospital, Singapore 119260, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2016,11,15]]},"reference":[{"key":"2021113010461611000_B1","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1007\/s00467-004-1438-8","article-title":"Atopy, serum IgE, and interleukin-13\u00a0in steroid-responsive nephrotic syndrome","volume":"19","author":"Cheung","year":"2004","journal-title":"Pediatr. Nephrol."},{"key":"2021113010461611000_B2","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1111\/j.1651-2227.2007.00154.x","article-title":"Atopy in childhood idiopathic nephrotic syndrome","volume":"96","author":"Salsano","year":"2007","journal-title":"Acta Paediatr."},{"key":"2021113010461611000_B3","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1002\/eji.1830250604","article-title":"Involvement of interleukin (IL)-13, but not IL-4, in spontaneous IgE and IgG4 production in nephrotic syndrome","volume":"25","author":"Kimata","year":"1995","journal-title":"Eur. J. Immunol."},{"key":"2021113010461611000_B4","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1007\/s004670050592","article-title":"Up-regulation of interleukin-4 and CD23\/FceRII in minimal change nephrotic syndrome","volume":"13","author":"Cho","year":"1999","journal-title":"Pediatr. Nephrol."},{"key":"2021113010461611000_B5","doi-asserted-by":"publisher","first-page":"945","DOI":"10.1053\/j.ajkd.2009.03.019","article-title":"Idiopathic nephrotic syndrome and atopy: is there a common link? Am","volume":"54","author":"Abdel-Hafez","year":"2009","journal-title":"J. Kidney Dis."},{"key":"2021113010461611000_B6","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1681\/ASN.V103529","article-title":"Th1 and Th2 cytokine mRNA profiles in childhood nephrotic syndrome: evidence for increased IL-13 mRNA expression in relapse","volume":"10","author":"Yap","year":"1999","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021113010461611000_B7","doi-asserted-by":"crossref","first-page":"S139","DOI":"10.2310\/6650.2005.X0004.343","article-title":"Overexpression of interleukin-13 induces minimal change-like nephropathy in rats and is associated with increased B7\u20131 expression in the glomeruli","volume":"54","author":"Lai","year":"2006","journal-title":"J. Invest. Med."},{"key":"2021113010461611000_B8","doi-asserted-by":"publisher","first-page":"1476","DOI":"10.1681\/ASN.2006070710","article-title":"Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats","volume":"18","author":"Lai","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021113010461611000_B9","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1172\/JCI200114629","article-title":"Caught flat-footed: podocyte damage and the molecular bases of focal glomerulosclerosis","volume":"108","author":"Kerjaschki","year":"2001","journal-title":"J. Clin. Invest."},{"key":"2021113010461611000_B10","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1146\/annurev-physiol-020911-153238","article-title":"Cell biology and pathology of podocytes","volume":"74","author":"Greka","year":"2012","journal-title":"Annu. Rev. Physiol."},{"key":"2021113010461611000_B11","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/74139","article-title":"Getting a foothold in nephrotic syndrome","volume":"24","author":"Somlo","year":"2000","journal-title":"Nat. Genet."},{"key":"2021113010461611000_B12","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1084\/jem.106.5.649","article-title":"An electron microscope study of the glomerulus in nephrosis, glomerulonephritis, and lupus erythematosus","volume":"106","author":"Farquhar","year":"1957","journal-title":"J. Exp. Med."},{"key":"2021113010461611000_B13","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1016\/j.tcb.2007.06.006","article-title":"Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton","volume":"17","author":"Faul","year":"2007","journal-title":"Trends Cell Biol."},{"key":"2021113010461611000_B14","doi-asserted-by":"publisher","first-page":"1390","DOI":"10.1172\/JCI20402","article-title":"Induction of B7\u20131\u00a0in podocytes is associated with nephrotic syndrome","volume":"113","author":"Reiser","year":"2004","journal-title":"J. Clin. Invest."},{"key":"2021113010461611000_B15","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1681\/ASN.2007080836","article-title":"Urinary CD80 excretion increases in idiopathic minimal-change disease","volume":"20","author":"Garin","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021113010461611000_B16","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1038\/ki.2010.143","article-title":"Urinary CD80 is elevated in minimal change disease but not in focal segmental glomerulosclerosis","volume":"78","author":"Garin","year":"2010","journal-title":"Kidney Int."},{"key":"2021113010461611000_B17","doi-asserted-by":"publisher","first-page":"1803","DOI":"10.1007\/s00467-013-2498-4","article-title":"Serum from minimal change patients in relapse increases CD80 expression in cultured podocytes","volume":"28","author":"Ishimoto","year":"2013","journal-title":"Pediatr. Nephrol."},{"key":"2021113010461611000_B18","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1093\/ndt\/gfs543","article-title":"Toll-like receptor 3 ligand, polyIC, induces proteinuria and glomerular CD80, and increases urinary CD80\u00a0in mice","volume":"28","author":"Ishimoto","year":"2013","journal-title":"Nephrol. Dial. Transplant."},{"key":"2021113010461611000_B19","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/nm.2261","article-title":"Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome","volume":"17","author":"Clement","year":"2011","journal-title":"Nat. Med."},{"key":"2021113010461611000_B20","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/nm.3396","article-title":"Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome","volume":"20","author":"Clement","year":"2014","journal-title":"Nat. Med."},{"key":"2021113010461611000_B21","doi-asserted-by":"publisher","first-page":"e38","DOI":"10.1093\/nar\/gkl024","article-title":"A novel normalization method for effective removal of systematic variation in microarray data","volume":"34","author":"Chua","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"2021113010461611000_B22","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources","volume":"4","author":"Huang","year":"2009","journal-title":"Nat. Protoc."},{"key":"2021113010461611000_B23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/nar\/gkn923","article-title":"Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists","volume":"37","author":"Huang","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"2021113010461611000_B24","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1681\/ASN.V133630","article-title":"A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression","volume":"13","author":"Saleem","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021113010461611000_B25","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1073\/pnas.98.2.646","article-title":"Conditional immortalization of freshly isolated human mammary fibroblasts and endothelial cells","volume":"98","author":"O'Hare","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010461611000_B26","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1007\/s00109-008-0399-y","article-title":"Mechanisms of angiotensin II signaling on cytoskeleton of podocytes","volume":"86","author":"Hsu","year":"2008","journal-title":"J. Mol. Med."},{"key":"2021113010461611000_B27","doi-asserted-by":"publisher","first-page":"e24640","DOI":"10.1371\/journal.pone.0024640","article-title":"Defining the molecular character of the developing and adult kidney podocyte","volume":"6","author":"Brunskill","year":"2011","journal-title":"PLoS One"},{"key":"2021113010461611000_B28","doi-asserted-by":"publisher","first-page":"e34907","DOI":"10.1371\/journal.pone.0034907","article-title":"Primary cultures of glomerular parietal epithelial cells or podocytes with proven origin","volume":"7","author":"Kabgani","year":"2012","journal-title":"PLoS One"},{"key":"2021113010461611000_B29","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1038\/sj.emboj.7601014","article-title":"Large-scale identification of genes implicated in kidney glomerulus development and function","volume":"25","author":"Takemoto","year":"2006","journal-title":"EMBO J."},{"key":"2021113010461611000_B30","doi-asserted-by":"publisher","first-page":"4755","DOI":"10.1128\/MCB.00730-13","article-title":"Rac1 activation in podocytes induces rapid foot process effacement and proteinuria","volume":"33","author":"Yu","year":"2013","journal-title":"Mol. Cell Biol."},{"key":"2021113010461611000_B31","doi-asserted-by":"publisher","first-page":"1621","DOI":"10.1681\/ASN.2010111146","article-title":"Activation of RhoA in podocytes induces focal segmental glomerulosclerosis","volume":"22","author":"Zhu","year":"2011","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021113010461611000_B32","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1038\/ki.2011.472","article-title":"Mechanisms of the proteinuria induced by Rho GTPases","volume":"81","author":"Wang","year":"2012","journal-title":"Kidney Int."},{"key":"2021113010461611000_B33","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1097\/01.ASN.0000057853.05686.89","article-title":"Homodimerization and heterodimerization of the glomerular podocyte proteins nephrin and NEPH1","volume":"14","author":"Gerke","year":"2003","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021113010461611000_B34","doi-asserted-by":"publisher","first-page":"19266","DOI":"10.1074\/jbc.M301279200","article-title":"Nephrin and Neph1 co-localize at the podocyte foot process intercellular junction and form cis hetero-oligomers","volume":"278","author":"Barletta","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021113010461611000_B35","doi-asserted-by":"publisher","first-page":"2347","DOI":"10.1093\/hmg\/ddq108","article-title":"A model organism approach: defining the role of Neph proteins as regulators of neuron and kidney morphogenesis","volume":"19","author":"Neumann-Haefelin","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"2021113010461611000_B36","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1172\/JCI7236","article-title":"Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate","volume":"106","author":"Wharram","year":"2000","journal-title":"J. Clin. Invest."},{"key":"2021113010461611000_B37","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1038\/nature04662","article-title":"Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes","volume":"440","author":"Jones","year":"2006","journal-title":"Nature"},{"key":"2021113010461611000_B38","doi-asserted-by":"publisher","first-page":"2035","DOI":"10.1128\/MCB.01770-07","article-title":"Phosphorylated YDXV motifs and Nck SH2\/SH3 adaptors act cooperatively to induce actin reorganization","volume":"28","author":"Blasutig","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"2021113010461611000_B39","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1016\/j.bbrc.2006.08.053","article-title":"Rat nephrin modulates cell morphology via the adaptor protein Nck","volume":"349","author":"Li","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021113010461611000_B40","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.1172\/JCI27414","article-title":"Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization","volume":"116","author":"Verma","year":"2006","journal-title":"J. Clin. Invest."},{"key":"2021113010461611000_B41","doi-asserted-by":"publisher","first-page":"1533","DOI":"10.1681\/ASN.2009010056","article-title":"Nck proteins maintain the adult glomerular filtration barrier","volume":"20","author":"Jones","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021113010461611000_B42","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1177\/002215549904700107","article-title":"Cytoskeletal and adhesive structural polarizations accompany IL-13-induced human macrophage fusion","volume":"47","author":"DeFife","year":"1999","journal-title":"J. Histochem. Cytochem."},{"key":"2021113010461611000_B43","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1172\/JCI200113557","article-title":"IL-13 alters mucociliary differentiation and ciliary beating of human respiratory epithelial cells","volume":"108","author":"Laoukili","year":"2001","journal-title":"J. Clin. Invest."},{"key":"2021113010461611000_B44","doi-asserted-by":"publisher","first-page":"1461","DOI":"10.1128\/MCB.20.5.1461-1477.2000","article-title":"Regulatory and signaling properties of the Vav family","volume":"20","author":"Bustelo","year":"2000","journal-title":"Mol. Cell. Biol."},{"key":"2021113010461611000_B45","first-page":"87","article-title":"Vav: Captain Hook for signal transduction? Crit","volume":"6","author":"Katzav","year":"1995","journal-title":"Rev. Oncog."},{"key":"2021113010461611000_B46","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1016\/j.it.2004.09.015","article-title":"The chemokine system in diverse forms of macrophage activation and polarization","volume":"25","author":"Mantovani","year":"2004","journal-title":"Trends Immunol."},{"key":"2021113010461611000_B47","doi-asserted-by":"publisher","first-page":"834","DOI":"10.4049\/jimmunol.174.2.834","article-title":"Transcriptional profiling reveals complex regulation of the monocyte IL-1 beta system by IL-13","volume":"174","author":"Scotton","year":"2005","journal-title":"J. Immunol."},{"key":"2021113010461611000_B48","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1046\/j.1365-2249.2003.02252.x","article-title":"Childhood nephrotic syndrome in relapse is associated with down-regulation of monocyte CD14 expression and lipopolysaccharide-induced tumour necrosis factor-alpha production","volume":"134","author":"Chen","year":"2003","journal-title":"Clin. Exp. Immunol."}],"container-title":["Clinical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/130\/24\/2317\/448590\/cs1302317.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/clinsci\/article-pdf\/130\/24\/2317\/448590\/cs1302317.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T06:34:07Z","timestamp":1638254047000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/clinsci\/article\/130\/24\/2317\/71498\/Novel-role-of-Vav1-Rac1-pathway-in-actin"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,15]]},"references-count":48,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2016,12,1]]}},"URL":"https:\/\/doi.org\/10.1042\/cs20160312","relation":{},"ISSN":["0143-5221","1470-8736"],"issn-type":[{"value":"0143-5221","type":"print"},{"value":"1470-8736","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,15]]}}}