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Title: Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE).
Austin Authors: Oldfield, M D;Bach, Leon A;Forbes, J M;Nikolic-Paterson, D;McRobert, A;Thallas, Vicki;Atkins, R C;Osicka, Tanya M;Jerums, George ;Cooper, Mark E
Affiliation: Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Australia
Issue Date: 1-Dec-2001
Publication information: The Journal of Clinical Investigation; 108(12): 1853-63
Abstract: Tubulointerstitial 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.
Gov't Doc #: 11748269
DOI: 10.1172/JCI11951
Type: Journal Article
Subjects: Actins.analysis
Binding Sites
Cell Differentiation.drug effects
Cells, Cultured
Diabetic Nephropathies.etiology
Epithelial Cells.physiology
Glycosylation End Products, Advanced.metabolism.pharmacology
Kidney Tubules, Proximal.cytology.drug effects
Rats, Inbred WKY
Rats, Sprague-Dawley
Receptors, Immunologic.physiology
Transforming Growth Factor beta.analysis
Appears in Collections:Journal articles

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