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dc.contributor.authorOldfield, M Den
dc.contributor.authorBach, Leon Aen
dc.contributor.authorForbes, J Men
dc.contributor.authorNikolic-Paterson, Den
dc.contributor.authorMcRobert, Aen
dc.contributor.authorThallas, Vickien
dc.contributor.authorAtkins, R Cen
dc.contributor.authorOsicka, Tanya Men
dc.contributor.authorJerums, Georgeen
dc.contributor.authorCooper, Mark Een
dc.identifier.citationThe Journal of Clinical Investigation; 108(12): 1853-63en
dc.description.abstractTubulointerstitial disease, a prominent phenomenon in diabetic nephropathy, correlates with decline in renal function. The underlying pathogenic link between chronic hyperglycemia and the development of tubulointerstitial injury has not been fully elucidated, but myofibroblast formation represents a key step in the development of tubulointerstitial fibrosis. RAGE, the receptor for advanced glycation end products (AGEs), induces the expression of TGF-beta and other cytokines that are proposed to mediate the transdifferentiation of epithelial cells to form myofibroblasts. Here we report specific binding of (125)I-AGE-BSA to cell membranes prepared from a rat proximal tubule cell line and show that the binding site was RAGE. AGE exposure induced dose-dependent epithelial-myofibroblast transdifferentiation determined by morphological changes, de novo alpha smooth-muscle actin expression, and loss of epithelial E-cadherin staining. These effects could be blocked with neutralizing Ab's to RAGE or to TGF-beta. Transdifferentiation was also apparent in the proximal tubules of diabetic rats and in a renal biopsy from a patient with type 1 diabetes. The AGE cross-link breaker, phenyl-4,5-dimethylthiazolium bromide (ALT 711) reduced transdifferentiation in diabetic rats in association with reduced tubular AGE and TGF-beta expression. This study provides a novel mechanism to explain the development of tubulointerstitial disease in diabetic nephropathy and provides a new treatment target.en
dc.subject.otherBinding Sitesen
dc.subject.otherCell Differentiation.drug effectsen
dc.subject.otherCells, Cultureden
dc.subject.otherDiabetic Nephropathies.etiologyen
dc.subject.otherEpithelial Cells.physiologyen
dc.subject.otherGlycosylation End Products, Advanced.metabolism.pharmacologyen
dc.subject.otherKidney Tubules, Proximal.cytology.drug effectsen
dc.subject.otherRats, Inbred WKYen
dc.subject.otherRats, Sprague-Dawleyen
dc.subject.otherReceptors, Immunologic.physiologyen
dc.subject.otherTransforming Growth Factor beta.analysisen
dc.titleAdvanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE).en
dc.typeJournal Articleen
dc.identifier.journaltitleThe Journal of clinical investigationen
dc.identifier.affiliationDepartment of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Australiaen
Appears in Collections:Journal articles

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