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Adenosine A2B Receptor Antagonism Interferes with TGF-β Cellular Signaling Through SMAD2/-3 and p65-Nf-κB in

Ignacio Arias1, Claudia Jara1, Pablo Mendoza-Soto1

  • 1Molecular Pathology Laboratory, Institute of Biochemistry and Microbiology, Science Faculty, Universidad Austral de Chile, Valdivia 5110566, Chile.

Cells
|June 25, 2025
PubMed

Insights

Blocking the adenosine A2B receptor (A2B) with MRS1754 prevents kidney cell changes and inflammation in diabetic rats. This approach offers a potential strategy for treating diabetic nephropathy by targeting fibrogenesis.

Area of Science:

  • Nephrology
  • Pharmacology
  • Molecular Biology

Background:

  • Diabetic nephropathy is characterized by fibrogenesis and podocyte injury.
  • Adenosine signaling, particularly via the adenosine A2B receptor (A2B), is implicated in diabetic kidney disease progression.

Purpose of the Study:

  • To investigate the therapeutic potential of adenosine A2B receptor antagonism in experimental diabetic nephropathy.
  • To elucidate the molecular mechanisms by which A2B receptor blockade affects podocyte transformation and inflammation.

Main Methods:

  • In vivo studies using diabetic rats treated with the A2B receptor antagonist MRS1754.
  • In vitro studies using human podocytes exposed to TGF-β and MRS1754.
  • Analysis of glomerular markers, inflammatory mediators, and signaling pathways (SMAD, NF-κB).

Main Results:

  • A2B receptor antagonism in vivo reduced markers of podocyte dedifferentiation (Snail, α-SMA) and preserved podocyte proteins (nephrin, ZO-1).
  • MRS1754 treatment decreased inflammatory mediators (MCP-1, CCL3) and TGF-β levels.
  • In vitro, A2B antagonism inhibited TGF-β-induced SMAD2/-3 phosphorylation and NF-κB activation, reducing Snail expression.

Conclusions:

  • Adenosine A2B receptor blockade effectively impedes the pathogenic TGF-β signaling cascade in diabetic glomerulopathy.
  • Targeting the A2B receptor offers a promising therapeutic strategy to alleviate podocyte injury and fibrogenesis in diabetic kidney disease.
Keywords:
TGF-beta 1adenosine receptorsdiabetic nephropathyglomerulosclerosis

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