Advanced glycation end products activate Smad signaling via TGF‐β‐dependent and ‐independent mechanisms: implications for diabetic renal and vascular disease

Abstract

While it is thought that advanced glycation end products (AGEs) act by stimulating transforming growth factor (TGF)‐β to mediate diabetic injury, we report that AGEs can activate TGF‐β signaling, Smads, and mediate diabetic scarring directly and independently of TGF‐β. AGEs activate Smad2/3 in renal and vascular cells at 5 min, peaking over 15–30 min before TGF‐β synthesis at 24 h and occurs in TGF‐β 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‐β‐dependent pathway. A substantial inhibition of AGE‐ induced Smad activation and collagen synthesis by ERK/p38 MAPK inhibitors, but not by TGF‐β blockade, suggests that the MAPK‐Smad signaling crosstalk pathway is a key mechanism in diabetic scarring. Prevention of AGE‐induced Smad activation and collagen synthesis by overexpression of Smad7 indicates that Smad signaling may play a critical role in diabetic complications. This is further supported by the findings that activation of Smad2/3 in human diabetic nephropathy and vasculopathy is associated with local deposition of AGEs and up‐ regulation of RAGE. Thus, AGEs act by activating Smad signaling to mediate diabetic complications via both TGF‐β‐dependent and ‐independent pathways, shedding new light on the pathogenesis of diabetic organ injury.