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Advanced Glycation End-Products Induce Tubular CTGF via TGF-β–Independent Smad3 Signaling

Arthur C.K. Chung^*, Haiyan Zhang, Yao-Zhong Kong, Jia-Ju Tan, Xiao R. Huang^*, Jeffrey B. Kopp and Hui Y. Lan^*

*Li Ka Shing Institute of Health Sciences and Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China;
First People's Foshan Hospital, Foshan, Guangdong, China; and
Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Correspondence: Dr. Hui Y. Lan, Department of Medicine and Therapeutics, and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong, China. Phone: 852-3763-6077; Fax: 852-2145-7190; E-mail: hylan{at}cuhk.edu.hk

Received for publication January 7, 2009. Accepted for publication September 23, 2009.

Advanced glycation end-products (AGEs) can induce expression of connective tissue growth factor (CTGF), which seems to promote the development of diabetic nephropathy, but the exact signaling mechanisms that mediate this induction are unknown. Here, AGEs induced CTGF expression in tubular epithelial cells (TECs) that either lacked the TGF-β1 gene or expressed dominant TGF-β receptor II, demonstrating independence of TGF-β. Furthermore, conditional knockout of the gene encoding TGF-β receptor II from the kidney did not prevent AGE-induced renal expression of CTGF and collagen I. More specific, AGEs induced CTGF expression via the receptor for AGEs-extracellular signal–regulated kinase (RAGE-ERK)/p38 mitogen-activated protein kinase–Smad cross-talk pathway because inhibition of this pathway by several methods (anti-RAGE antibody, specific inhibitors, or dominant negative adenovirus to ERK1/2 and p38) blocked this induction. Overexpressing Smad7 abolished AGE-induced Smad3 phosphorylation and CTGF expression, demonstrating the necessity for activation of Smad signaling in this process. More important, knockdown of either Smad3 or Smad2 demonstrated that Smad3 but not Smad2 is essential for CTGF induction in response to AGEs. In conclusion, AGEs induce tubular CTGF expression via the TGF-β–independent RAGE-ERK/p38-Smad3 cross-talk pathway. These data suggest that overexpression of Smad7 or targeting Smad3 may have therapeutic potential for diabetic nephropathy.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673