Advanced glycation end products activate Smad signaling via TGF-beta-dependent and -independent mechanisms: implications for diabetic renal and vascular disease
JH Li, XR Huang, HJ Zhu, M Oldfield, M Cooper, LD Truong, RJ Johnson, HY Lan
FASEB JOURNAL | FEDERATION AMER SOC EXP BIOL | Published : 2004
While it is thought that advanced glycation end products (AGEs) act by stimulating transforming growth factor (TGF)-beta to mediate diabetic injury, we report that AGEs can activate TGF-beta signaling, Smads, and mediate diabetic scarring directly and independently of TGF-beta. AGEs activate Smad2/3 in renal and vascular cells at 5 min, peaking over 15-30 min before TGF-beta synthesis at 24 h and occurs in TGF-beta receptor I and II mutant cells. This is mediated by RAGE and ERK/p38 mitogen-activated protein kinases (MAPKs). In addition, AGEs also activate Smads at 24 h via the classic TGF-beta-dependent pathway. A substantial inhibition of AGE-induced Smad activation and collagen synthesis ..View full abstract
Awarded by Juvenile Diabetes Research Foundation (JDRF)
Awarded by Texas Advanced Technology Program
Awarded by National Health & Medical Research Council
This work is supported by grants from the Juvenile Diabetes Research Foundation (JDRF 1-2001-596 and 4-1999-821), Texas Advanced Technology Program (004949-0005-2001), and from the National Health & Medical Research Council (164812).