{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T14:32:23Z","timestamp":1783434743109,"version":"3.54.6"},"reference-count":53,"publisher":"American Diabetes Association","issue":"6","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":3751,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,6,1]]},"abstract":"<jats:sec>\n                  <jats:title>OBJECTIVE<\/jats:title>\n                  <jats:p>Diabetic nephropathy is associated with dedifferentiation of podocytes, losing the specialized features required for efficient glomerular function and acquiring a number of profibrotic, proinflammatory, and proliferative features. These result from tight junction and cytoskeletal rearrangement, augmented proliferation, and apoptosis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                  <jats:p>Experiments were performed in conditionally immortalized human podocytes developed by transfection with the temperature-sensitive SV40-T gene. Cells were then cultured in the presence of transforming growth factor (TGF)-\u03b21 or angiotensin II in the presence or absence of a selective inhibitor of the TGF-\u03b2 type I receptor kinase, SB-431542. Gene and protein expression were then examined by real-time RT-PCR and immunofluorescence, and correlated with changes observed in vivo in experimental diabetes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>Treatment of cells with TGF-\u03b21 resulted in dynamic changes in their morphology, starting with retraction and shortening of foot processes and finishing with the formation of broad and complex tight junctions between adjacent podocytes. This dedifferentiation was also associated with dose- and time-dependent reduction in the expression of glomerular epithelial markers (nephrin, p-cadherin, zonnula occludens-1) and increased expression of mesenchymal markers (\u03b1\u2212smooth muscle actin, vimentin, nestin), matrix components (fibronectin, collagen I, and collagen IV \u03b13), cellular proliferation, and apoptosis. The induction of diabetes in mice was also associated with similar changes in morphology, protein expression, and proliferation in glomerular podocytes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>In response to TGF-\u03b2 and other TGF-dependent stimuli, mature podocytes undergo dedifferentiation that leads to effacement of foot processes, morphologic flattening, and increased formation of intercellular tight junctions. This simplification of their phenotype to a more embryonic form is also associated with reentry of mature podocytes into the cell cycle, which results in enhanced proliferation and apoptosis. These \u201cpathoadaptive\u201d changes are seen early in the diabetic glomerulus and ultimately contribute to albuminuria, glomerulosclerosis, and podocytopenia.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/db10-1110","type":"journal-article","created":{"date-parts":[[2011,4,27]],"date-time":"2011-04-27T02:20:34Z","timestamp":1303870834000},"page":"1779-1788","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":102,"title":["Dedifferentiation of Immortalized Human Podocytes in Response to Transforming Growth Factor-\u03b2"],"prefix":"10.2337","volume":"60","author":[{"given":"Michal","family":"Herman-Edelstein","sequence":"first","affiliation":[{"name":"JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia"},{"name":"Department of Nephrology and Hypertension, Rabin Medical Center-Hasharon Hospital, Ackler School of Medicine Tel-Aviv University, Petach-Tikva, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merlin C.","family":"Thomas","sequence":"additional","affiliation":[{"name":"JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicki","family":"Thallas-Bonke","sequence":"additional","affiliation":[{"name":"JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moin","family":"Saleem","sequence":"additional","affiliation":[{"name":"Academic and Children\u2019s Renal Unit, University of Bristol, Bristol, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark E.","family":"Cooper","sequence":"additional","affiliation":[{"name":"JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip","family":"Kantharidis","sequence":"additional","affiliation":[{"name":"JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2011,5,21]]},"reference":[{"key":"2022031209361119200_B1","doi-asserted-by":"crossref","first-page":"39","DOI":"10.2174\/157339908783502370","article-title":"Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy","volume":"4","author":"Ziyadeh","year":"2008","journal-title":"Curr Diabetes Rev"},{"key":"2022031209361119200_B2","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.2337\/diabetes.54.6.1626","article-title":"From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy","volume":"54","author":"Wolf","year":"2005","journal-title":"Diabetes"},{"key":"2022031209361119200_B3","doi-asserted-by":"crossref","first-page":"S36","DOI":"10.1038\/sj.ki.5002384","article-title":"Podocyte biology in diabetic nephropathy","author":"Li","year":"2007","journal-title":"Kidney Int Suppl"},{"key":"2022031209361119200_B4","doi-asserted-by":"crossref","first-page":"F1777","DOI":"10.1152\/ajprenal.00187.2007","article-title":"Evidence for restriction of fluid and solute movement across the glomerular capillary wall by the subpodocyte space","volume":"293","author":"Salmon","year":"2007","journal-title":"Am J Physiol Renal Physiol"},{"key":"2022031209361119200_B5","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1053\/j.ajkd.2009.07.003","article-title":"Epithelial-mesenchymal transition and podocyte loss in diabetic kidney disease","volume":"54","author":"Reidy","year":"2009","journal-title":"Am J Kidney Dis"},{"key":"2022031209361119200_B6","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1681\/ASN.2004060436","article-title":"Transient overexpression of TGF-beta1 induces epithelial mesenchymal transition in the rodent peritoneum","volume":"16","author":"Margetts","year":"2005","journal-title":"J Am Soc Nephrol"},{"key":"2022031209361119200_B7","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1053\/j.ajkd.2009.05.009","article-title":"Epithelial-mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy","volume":"54","author":"Yamaguchi","year":"2009","journal-title":"Am J Kidney Dis"},{"key":"2022031209361119200_B8","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1038\/sj.ki.5000410","article-title":"The podocyte\u2019s response to injury: role in proteinuria and glomerulosclerosis","volume":"69","author":"Shankland","year":"2006","journal-title":"Kidney Int"},{"key":"2022031209361119200_B9","first-page":"F563","article-title":"Early role of Fsp1 in epithelial-mesenchymal transformation","volume":"273","author":"Okada","year":"1997","journal-title":"Am J Physiol"},{"key":"2022031209361119200_B10","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1016\/S0272-6386(01)80132-3","article-title":"Interleukin-1 induces tubular epithelial-myofibroblast transdifferentiation through a transforming growth factor-beta1-dependent mechanism in vitro","volume":"37","author":"Fan","year":"2001","journal-title":"Am J Kidney Dis"},{"key":"2022031209361119200_B11","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1046\/j.1523-1755.2002.00333.x","article-title":"Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation","volume":"61","author":"Strutz","year":"2002","journal-title":"Kidney Int"},{"key":"2022031209361119200_B12","doi-asserted-by":"crossref","first-page":"S246","DOI":"10.1097\/01.ASN.0000077411.98742.54","article-title":"Reactive oxygen species and matrix remodeling in diabetic kidney","volume":"14","author":"Ha","year":"2003","journal-title":"J Am Soc Nephrol"},{"key":"2022031209361119200_B13","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1097\/00041552-200301000-00005","article-title":"Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells","volume":"12","author":"Lan","year":"2003","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"2022031209361119200_B14","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1016\/S0002-9440(10)62533-3","article-title":"Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis","volume":"159","author":"Yang","year":"2001","journal-title":"Am J Pathol"},{"key":"2022031209361119200_B15","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1172\/JCI200320530","article-title":"Epithelial-mesenchymal transition and its implications for fibrosis","volume":"112","author":"Kalluri","year":"2003","journal-title":"J Clin Invest"},{"key":"2022031209361119200_B16","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1083\/jcb.200601018","article-title":"The epithelial-mesenchymal transition: new insights in signaling, development, and disease","volume":"172","author":"Lee","year":"2006","journal-title":"J Cell Biol"},{"key":"2022031209361119200_B17","doi-asserted-by":"crossref","first-page":"5764","DOI":"10.1038\/sj.onc.1208927","article-title":"TGF-beta and epithelial-to-mesenchymal transitions","volume":"24","author":"Zavadil","year":"2005","journal-title":"Oncogene"},{"key":"2022031209361119200_B18","doi-asserted-by":"crossref","first-page":"S38","DOI":"10.1016\/j.diabres.2008.09.016","article-title":"Different roles for TGF-beta and VEGF in the pathogenesis of the cardinal features of diabetic nephropathy","volume":"82","author":"Ziyadeh","year":"2008","journal-title":"Diabetes Res Clin Pract"},{"key":"2022031209361119200_B19","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1093\/ndt\/gfh837","article-title":"Angiotensin II stimulates alpha3(IV) collagen production in mouse podocytes via TGF-beta and VEGF signalling: implications for diabetic glomerulopathy","volume":"20","author":"Chen","year":"2005","journal-title":"Nephrol Dial Transplant"},{"key":"2022031209361119200_B20","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1046\/j.1523-1755.2002.00528.x","article-title":"Effects of high glucose and TGF-beta1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes","volume":"62","author":"Iglesias-de la Cruz","year":"2002","journal-title":"Kidney Int"},{"key":"2022031209361119200_B21","doi-asserted-by":"crossref","first-page":"450","DOI":"10.2337\/diab.42.3.450","article-title":"mRNA expression of growth factors in glomeruli from diabetic rats","volume":"42","author":"Nakamura","year":"1993","journal-title":"Diabetes"},{"key":"2022031209361119200_B22","doi-asserted-by":"crossref","first-page":"3211","DOI":"10.1681\/ASN.2004121055","article-title":"TGF-beta concentration specifies differential signaling profiles of growth arrest\/differentiation and apoptosis in podocytes","volume":"16","author":"Wu","year":"2005","journal-title":"J Am Soc Nephrol"},{"key":"2022031209361119200_B23","doi-asserted-by":"crossref","first-page":"225","DOI":"10.2337\/diabetes.55.01.06.db05-0894","article-title":"Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy","volume":"55","author":"Susztak","year":"2006","journal-title":"Diabetes"},{"key":"2022031209361119200_B24","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1172\/JCI200112367","article-title":"Apoptosis in podocytes induced by TGF-beta and Smad7","volume":"108","author":"Schiffer","year":"2001","journal-title":"J Clin Invest"},{"key":"2022031209361119200_B25","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":"2022031209361119200_B26","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1007\/s00125-003-1121-9","article-title":"Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy","volume":"46","author":"Davis","year":"2003","journal-title":"Diabetologia"},{"key":"2022031209361119200_B27","first-page":"710","article-title":"IL-6 increases endothelial permeability in vitro","volume":"131","author":"Maruo","year":"1992","journal-title":"Endocrinology"},{"key":"2022031209361119200_B28","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1097\/01.ASN.0000133025.23732.46","article-title":"Accelerated nephropathy in diabetic apolipoprotein e-knockout mouse: role of advanced glycation end products","volume":"15","author":"Lassila","year":"2004","journal-title":"J Am Soc Nephrol"},{"key":"2022031209361119200_B29","doi-asserted-by":"crossref","first-page":"299","DOI":"10.2353\/ajpath.2008.070057","article-title":"Epithelial-to-mesenchymal transition is a potential pathway leading to podocyte dysfunction and proteinuria","volume":"172","author":"Li","year":"2008","journal-title":"Am J Pathol"},{"key":"2022031209361119200_B30","first-page":"48","article-title":"Pathogenesis of polycation-induced alterations (\u201cfusion\u201d) of glomerular epithelium","volume":"36","author":"Seiler","year":"1977","journal-title":"Lab Invest"},{"key":"2022031209361119200_B31","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.cmet.2010.08.015","article-title":"Insulin signaling to the glomerular podocyte is critical for normal kidney function","volume":"12","author":"Welsh","year":"2010","journal-title":"Cell Metab"},{"key":"2022031209361119200_B32","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1172\/JCI36183","article-title":"Biomarkers for epithelial-mesenchymal transitions","volume":"119","author":"Zeisberg","year":"2009","journal-title":"J Clin Invest"},{"key":"2022031209361119200_B33","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.2337\/db09-1736","article-title":"E-cadherin expression is regulated by miR-192\/215 by a mechanism that is independent of the profibrotic effects of transforming growth factor-beta","volume":"59","author":"Wang","year":"2010","journal-title":"Diabetes"},{"key":"2022031209361119200_B34","doi-asserted-by":"crossref","first-page":"R1856","DOI":"10.1152\/ajpregu.00862.2007","article-title":"Claudin-6 localized in tight junctions of rat podocytes","volume":"294","author":"Zhao","year":"2008","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2022031209361119200_B35","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1681\/ASN.2008101117","article-title":"Slit diaphragms contain tight junction proteins","volume":"20","author":"Fukasawa","year":"2009","journal-title":"J Am Soc Nephrol"},{"key":"2022031209361119200_B36","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1681\/ASN.2004080679","article-title":"Cultured podocytes establish a size-selective barrier regulated by specific signaling pathways and demonstrate synchronized barrier assembly in a calcium switch model of junction formation","volume":"16","author":"Hunt","year":"2005","journal-title":"J Am Soc Nephrol"},{"key":"2022031209361119200_B37","doi-asserted-by":"crossref","first-page":"894","DOI":"10.2337\/diabetes.55.04.06.db05-0355","article-title":"ZO-1 expression and phosphorylation in diabetic nephropathy","volume":"55","author":"Rincon-Choles","year":"2006","journal-title":"Diabetes"},{"key":"2022031209361119200_B38","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/sj.ki.5002291","article-title":"Podocytes in culture: past, present, and future","volume":"72","author":"Shankland","year":"2007","journal-title":"Kidney Int"},{"key":"2022031209361119200_B39","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1159\/000102520","article-title":"Culture methods of glomerular podocytes","volume":"30","author":"Krtil","year":"2007","journal-title":"Kidney Blood Press Res"},{"key":"2022031209361119200_B40","doi-asserted-by":"crossref","first-page":"797","DOI":"10.2353\/ajpath.2009.080227","article-title":"Podocyte repopulation contributes to regression of glomerular injury induced by ACE inhibition","volume":"174","author":"Macconi","year":"2009","journal-title":"Am J Pathol"},{"key":"2022031209361119200_B41","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1159\/000013580","article-title":"The urinary podocyte as a marker for the differential diagnosis of idiopathic focal glomerulosclerosis and minimal-change nephrotic syndrome","volume":"20","author":"Nakamura","year":"2000","journal-title":"Am J Nephrol"},{"key":"2022031209361119200_B42","doi-asserted-by":"crossref","first-page":"2830","DOI":"10.1681\/ASN.2005080841","article-title":"Role of podocytes in focal sclerosis: defining the point of no return","volume":"16","author":"Kretzler","year":"2005","journal-title":"J Am Soc Nephrol"},{"key":"2022031209361119200_B43","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1159\/000285844","article-title":"Effects of TGF-beta on podocyte growth and disease progression in proliferative podocytopathies","volume":"33","author":"Lee","year":"2010","journal-title":"Kidney Blood Press Res"},{"key":"2022031209361119200_B44","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1681\/ASN.2009060663","article-title":"NFkappaB promotes inflammation, coagulation, and fibrosis in the aging glomerulus","volume":"21","author":"Wiggins","year":"2010","journal-title":"J Am Soc Nephrol"},{"key":"2022031209361119200_B45","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.2337\/diab.42.11.1673","article-title":"Transforming growth factor-beta 1 enhances glomerular collagen synthesis in diabetic rats","volume":"42","author":"Bollineni","year":"1993","journal-title":"Diabetes"},{"key":"2022031209361119200_B46","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1111\/j.1464-5491.2004.01242.x","article-title":"Transforming growth factor beta at clinical onset of type 1 diabetes mellitus. A pilot study","volume":"21","author":"Flores","year":"2004","journal-title":"Diabet Med"},{"key":"2022031209361119200_B47","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.2337\/diacare.19.10.1113","article-title":"Elevated plasma levels of transforming growth factor-beta 1 in NIDDM","volume":"19","author":"Pfeiffer","year":"1996","journal-title":"Diabetes Care"},{"key":"2022031209361119200_B48","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1161\/hy0102.100536","article-title":"Renal interstitial fluid concentrations of angiotensins I and II in anesthetized rats","volume":"39","author":"Nishiyama","year":"2002","journal-title":"Hypertension"},{"key":"2022031209361119200_B49","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/ncb1400","article-title":"Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling","volume":"8","author":"Asanuma","year":"2006","journal-title":"Nat Cell Biol"},{"key":"2022031209361119200_B50","doi-asserted-by":"crossref","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":"2022031209361119200_B51","doi-asserted-by":"crossref","first-page":"F959","DOI":"10.1152\/ajprenal.00559.2007","article-title":"The molecular and functional phenotype of glomerular podocytes reveals key features of contractile smooth muscle cells","volume":"295","author":"Saleem","year":"2008","journal-title":"Am J Physiol Renal Physiol"},{"key":"2022031209361119200_B52","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1172\/JCI12539","article-title":"Loss of glomerular foot processes is associated with uncoupling of podocalyxin from the actin cytoskeleton","volume":"108","author":"Takeda","year":"2001","journal-title":"J Clin Invest"},{"key":"2022031209361119200_B53","doi-asserted-by":"crossref","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"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/60\/6\/1779\/664082\/1779.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/60\/6\/1779\/664082\/1779.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:24:27Z","timestamp":1667406267000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/60\/6\/1779\/14199\/Dedifferentiation-of-Immortalized-Human-Podocytes"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,5,21]]},"references-count":53,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2011,5,21]]},"published-print":{"date-parts":[[2011,6,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db10-1110","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,5,21]]}}}