Advanced glycation end-products induce tubular CTGF via TGF-beta-independent Smad3 signaling.
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.
Chung
Arthur C K
AC
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.
Zhang
Haiyan
H
Kong
Yao-Zhong
YZ
Tan
Jia-Ju
JJ
Huang
Xiao R
XR
Kopp
Jeffrey B
JB
Lan
Hui Y
HY
D000818:Animals; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D051381:Rats; D020239:Receptor Cross-Talk / Q000502:physiology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D051906:Smad7 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D024042:Collagen Type I; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051899:Smad2 Protein; D051900:Smad3 Protein; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D048051:p38 Mitogen-Activated Protein Kinases