Adenosine A(2A) receptor activation prevents progressive kidney fibrosis in a model of immune-associated chronic inflammation

作者：Garcia Gabriela E^*; Truong Luan D; Chen Jiang Fan; Johnson Richard J; Feng Lili

来源：Kidney International, 2011, 80(4): 378-388.

DOI：10.1038/ki.2011.101

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

Crescentic glomerulonephritis (GN) in Wistar-Kyoto rats progresses to lethal kidney failure by macrophage (M phi)-mediated mechanisms. M phi s in nephritic glomeruli express adenosine A(2A) receptors (A(2A)Rs), the activation of which suppresses inflammation. Here, we pharmacologically activated the A(2A)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 phi infiltration was reduced by 83%. There was also a marked improvement in glomerular lesion histology, as well as decreased proteinuria. A(2A)R activation significantly reduced type I, III, and IV collagen deposition, and E-cadherin expression was restored in association with a reduction of alpha-smooth muscle actin-positive myofibroblasts in the interstitium and glomeruli. In contrast, pharmacological inactivation of A(2A)Rs increased glomerular crescent formation, type I, III, and IV collagen expression, and enhanced E-cadherin loss. Activation of A(2A)Rs suppressed the expression of the M phi-linked glomerular damage mediators, transforming growth factor-beta, osteopontin-1, thrombospondin-1, and tissue inhibitor of metalloproteinase-1. Thus, A(2A)R activation can arrest GN and prevent progressive fibrosis in established pathological lesions. Kidney International (2011) 80, 378-388; doi:10.1038/ki.2011.101; published online 20 April 2011

• 出版日期2011-8