Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease

Burns, Wendy C., Twigg, Stephen M., Forbes, Josephine M., Pete, Josefa, Tikellis, Christos, Thallas-Bonke, Vicki, Thomas, Merlin C., Cooper, Mark E. and Kantharidis, Phillip (2006) Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease. Journal of the American Society of Nephrology, 17 9: 2484-2494. doi:10.1681/ASN.2006050525


Author Burns, Wendy C.
Twigg, Stephen M.
Forbes, Josephine M.
Pete, Josefa
Tikellis, Christos
Thallas-Bonke, Vicki
Thomas, Merlin C.
Cooper, Mark E.
Kantharidis, Phillip
Title Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease
Journal name Journal of the American Society of Nephrology   Check publisher's open access policy
ISSN 1046-6673
1533-3450
Publication date 2006-09-01
Year available 2006
Sub-type Article (original research)
DOI 10.1681/ASN.2006050525
Open Access Status Not yet assessed
Volume 17
Issue 9
Start page 2484
End page 2494
Total pages 11
Place of publication Washington, DC, United States
Publisher American Society of Nephrology
Language eng
Formatted abstract
Epithelial-to-mesenchymal transition (EMT) of tubular cells contributes to the renal accumulation of matrix protein that is associated with diabetic nephropathy. Both TGF-β1 and advanced glycation end products (AGE) are able to induce EMT in cell culture. This study examined the role of the prosclerotic growth factor connective tissue growth factor (CTGF) as a downstream mediator of these processes. EMT was assessed by the expression of α-smooth muscle actin, vimentin, E-cadherin, and matrix proteins and the induction of a myofibroblastic phenotype. CTGF, delivered in an adenovirus or as recombinant human CTGF (250 ng/ml), was shown to induce a partial EMT. This was not blocked by neutralizing anti-TGF-β1 antibodies, suggesting that this action was TGF-β1 independent. NRK-52E cells that were exposed to AGE-modified BSA (AGE-BSA; 40 μM) or TGF-β1 (10 ng/ml) also underwent EMT. This was associated with the induction of CTGF gene and protein expression. Transfection with siRNA to CTGF was able to attenuate EMT-associated phenotypic changes after treatment with AGE or TGF-β1. These in vitro effects correlate with the in vivo finding of increased CTGF expression in the diabetic kidney, which co-localizes on the tubular epithelium with sites of EMT. In addition, inhibition of AGE accumulation was able to reduce CTGF expression and attenuate renal fibrosis in experimental diabetes. These findings suggest that CTGF represents an important independent mediator of tubular EMT, downstream of the actions of AGE or TGF-β1. This interaction is likely to play an important role in progressive diabetic nephropathy and strengthens the rationale to consider CTGF as a potential target for the treatment of diabetic nephropathy. 
Keyword Urology & Nephrology
Urology & Nephrology
UROLOGY & NEPHROLOGY
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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