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

• Published in: Journal of the American Society of Nephrology 2010-02, Vol.21 (2), p.249-260
• Main Authors: CHUNG, Arthur C. K, HAIYAN ZHANG, KONG, Yao-Zhong, TAN, Jia-Ju, HUANG, Xiao R, KOPP, Jeffrey B, LAN, Hui Y
• Format: Article
• Language: English
• Subjects: Animals; Basic Research; Biological and medical sciences; Cell Line; Collagen Type I - metabolism; Connective Tissue Growth Factor - metabolism; Glycation End Products, Advanced - metabolism; Kidney Tubules - metabolism; Kidney Tubules - pathology; Medical sciences; Mice; Mice, Knockout; Models, Animal; Nephrology. Urinary tract diseases; p38 Mitogen-Activated Protein Kinases - metabolism; Rats; Receptor Cross-Talk - physiology; Receptor for Advanced Glycation End Products; Receptors, Immunologic - metabolism; Signal Transduction - physiology; Smad2 Protein - genetics; Smad2 Protein - metabolism; Smad3 Protein - genetics; Smad3 Protein - metabolism; Smad7 Protein - metabolism; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2009010018

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-beta1 gene or expressed dominant TGF-beta receptor II, demonstrating independence of TGF-beta. Furthermore, conditional knockout of the gene encoding TGF-beta 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-beta-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.