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Advanced glycation end-products induce tubular CTGF via TGF-beta-independent Smad3 signaling

Arthur C K Chung1, Haiyan Zhang, Yao-Zhong Kong

  • 1Department 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.

Journal of the American Society of Nephrology : JASN
|December 5, 2009
PubMed

Insights

Advanced glycation end-products (AGEs) trigger connective tissue growth factor (CTGF) in kidney cells independently of TGF-beta. This occurs via the RAGE-ERK/p38-Smad3 pathway, suggesting Smad3 as a therapeutic target for diabetic nephropathy.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Diabetology

Background:

  • Advanced glycation end-products (AGEs) are implicated in diabetic nephropathy pathogenesis.
  • Connective tissue growth factor (CTGF) is upregulated in diabetic nephropathy.
  • The precise signaling pathways linking AGEs to CTGF induction remain unclear.

Purpose of the Study:

  • To elucidate the signaling mechanisms by which AGEs induce CTGF expression in renal tubular epithelial cells (TECs).
  • To investigate the role of transforming growth factor-beta (TGF-beta) signaling in AGE-induced CTGF expression.
  • To identify key molecular players in the AGEs-CTGF axis for potential therapeutic targeting.

Main Methods:

  • AGEs were applied to TECs with manipulated TGF-beta signaling (gene knockout, dominant-negative receptor).
  • Inhibition of the receptor for AGEs (RAGE), extracellular signal-regulated kinase (ERK), and p38 mitogen-activated protein kinase (MAPK) pathways was performed.
  • Smad signaling components (Smad7, Smad2, Smad3) were modulated using overexpression or knockdown techniques.
  • CTGF expression, Smad phosphorylation, and Smad2/3 involvement were assessed.

Main Results:

  • AGE-induced CTGF expression in TECs was independent of TGF-beta signaling.
  • Conditional knockout of TGF-beta receptor II in kidneys did not prevent AGE-induced CTGF and collagen I expression.
  • Inhibition of RAGE, ERK, or p38 significantly blocked AGE-induced CTGF expression.
  • Overexpression of Smad7 abolished AGE-induced Smad3 phosphorylation and CTGF upregulation.
  • Knockdown of Smad3, but not Smad2, prevented CTGF induction by AGEs.

Conclusions:

  • AGEs induce tubular CTGF expression through a TGF-beta-independent pathway involving RAGE, ERK/p38 MAPK, and Smad3.
  • Smad3 is a critical mediator in the AGEs-induced CTGF signaling cascade.
  • Targeting Smad3 or utilizing Smad7 may offer novel therapeutic strategies for diabetic nephropathy.

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