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RAGE Deletion Confers Renoprotection by Reducing Responsiveness to Transforming Growth Factor-β and Increasing

Shinji Hagiwara1,2, Karly Sourris1,2, Mark Ziemann1,2

  • 1Department of Diabetes, Monash University, Melbourne, Australia.

Diabetes
|February 17, 2018
PubMed

Insights

Receptor of advanced glycation end products (RAGE) deletion in mice surprisingly increased fibrotic and inflammatory markers but conferred protection against diabetic nephropathy by reducing growth factor response and promoting cell survival.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Diabetology

Background:

  • Diabetic nephropathy (DN) involves complex injurious pathways, with receptor of advanced glycation end products (RAGE) signaling implicated.
  • The precise role of RAGE in DN pathogenesis remains incompletely understood.

Purpose of the Study:

  • To investigate the functional consequences of RAGE deletion on kidney cells and in the context of diabetic nephropathy.
  • To elucidate the mechanisms underlying RAGE's contribution to DN progression.

Main Methods:

  • Utilized RAGE knockout (RAGE-/-) and wild-type (WT) mice, primary mouse mesangial cells (MCs).
  • Performed RNA sequencing, assessed fibrotic and inflammatory markers, evaluated responsiveness to transforming growth factor-β (TGF-β), and analyzed apoptosis susceptibility.
  • Conducted RAGE restoration experiments in RAGE-/- MCs.

Main Results:

  • RAGE deletion led to increased expression of fibrotic markers (collagen I/IV, fibronectin) and MCP-1 in MCs and kidney cortex.
  • Despite increased fibrotic markers, RAGE-/- mice showed decreased TGF-β responsiveness.
  • RAGE deletion promoted a proliferative MC phenotype and reduced apoptosis, suggesting a protective effect against injury.

Conclusions:

  • RAGE knockout mice exhibit protection against DN, partly due to reduced growth factor sensitivity and an anti-apoptotic MC phenotype.
  • RAGE plays a critical role in modulating kidney sensitivity to injurious stimuli like prosclerotic cytokines in DN.

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