Adenosine A2A receptor activation prevents progressive kidney fibrosis in a model of immune-associated chronic inflammation

Gabriela E. Garcia, Luan Truong, Jiang Fan Chen, Richard J. Johnson, Lili Feng

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Crescentic glomerulonephritis (GN) in Wistar-Kyoto rats progresses to lethal kidney failure by macrophage (M)-mediated mechanisms. Ms in nephritic glomeruli express adenosine A2A receptors (A2A Rs), the activation of which suppresses inflammation. Here, we pharmacologically activated the A2A Rs with a selective agonist, CGS 21680, and inactivated them with a selective antagonist, ZM241385, to test the effects on established GN. When activation was delayed until antiglomerular basement membrane GN and extracellular matrix deposition were established, glomerular M infiltration was reduced by 83%. There was also a marked improvement in glomerular lesion histology, as well as decreased proteinuria. A2A R activation significantly reduced type I, III, and IV collagen deposition, and E-cadherin expression was restored in association with a reduction of α-smooth muscle actin-positive myofibroblasts in the interstitium and glomeruli. In contrast, pharmacological inactivation of A2A Rs increased glomerular crescent formation, type I, III, and IV collagen expression, and enhanced E-cadherin loss. Activation of A2A Rs suppressed the expression of the M-linked glomerular damage mediators, transforming growth factor-Β, osteopontin-1, thrombospondin-1, and tissue inhibitor of metalloproteinase-1. Thus, A2A R activation can arrest GN and prevent progressive fibrosis in established pathological lesions.

Original languageEnglish (US)
Pages (from-to)378-388
Number of pages11
JournalKidney international
Volume80
Issue number4
DOIs
StatePublished - Aug 2 2011

Keywords

  • adenosine receptors
  • glomerulonephritis
  • inflammation
  • kidney fibrosis
  • macrophages

ASJC Scopus subject areas

  • Nephrology

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