TY - JOUR
T1 - Adenosine A2A receptor activation prevents progressive kidney fibrosis in a model of immune-associated chronic inflammation
AU - Garcia, Gabriela E.
AU - Truong, Luan
AU - Chen, Jiang Fan
AU - Johnson, Richard J.
AU - Feng, Lili
N1 - Funding Information:
Dr Lili Feng unfortunately died before we finished this study. She was a model scientist demonstrating equal creativity and talent that made a great contribution to basic medical science, in particular toward understanding the pathophysiology of kidney inflammation. Dr Feng was a truly extraordinary woman with a wonderful spirit that will be always missed. This study is dedicated to her memory. We gratefully thank Dr W Mitch for his helpful comments and discussions regarding this paper. This work was supported in part by the National Institute of Health George O’Brien Center Grant (P50 DK064233, to GEG, LDT, and LF), National Institute of Health 5R21AT002140 (to LF), and Norman S Coplon Grant (to GEG).
PY - 2011/8/2
Y1 - 2011/8/2
N2 - 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.
AB - 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.
KW - adenosine receptors
KW - glomerulonephritis
KW - inflammation
KW - kidney fibrosis
KW - macrophages
UR - http://www.scopus.com/inward/record.url?scp=85027927189&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85027927189&partnerID=8YFLogxK
U2 - 10.1038/ki.2011.101
DO - 10.1038/ki.2011.101
M3 - Article
C2 - 21508927
AN - SCOPUS:85027927189
SN - 0085-2538
VL - 80
SP - 378
EP - 388
JO - Kidney international
JF - Kidney international
IS - 4
ER -