title: Adenosine A(2A) receptor activation prevents progressive kidney fibrosis in a model of immune-associated chronic inflammation.
abstract: Crescentic glomerulonephritis (GN) in Wistar-Kyoto rats progresses to lethal kidney failure by macrophage (Mφ)-mediated mechanisms. Mφs 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 Mφ 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 α-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 Mφ-linked glomerular damage mediators, transforming growth factor-β, 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.
authors.affiliation: Division of Nephrology, Department of Medicine, Baylor College of Medicine, Houston, Texas 80045, USA. Gabriela.garcia@ucdenver.edu
authors.forename: Gabriela E
authors.initials: GE
authors.lastname: Garcia
authors.forename: Luan D
authors.initials: LD
authors.lastname: Truong
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
authors.forename: Lili
authors.initials: L
authors.lastname: Feng
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology*; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001323:Autoantibodies; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005355:Fibrosis; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D043705:Receptor, Adenosine A2A / Q000187:drug effects* / Q000378:metabolism; D012720:Severity of Illness Index; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000893:Anti-Inflammatory Agents; D001323:Autoantibodies; D016326:Extracellular Matrix Proteins; D018836:Inflammation Mediators; D010627:Phenethylamines; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; C051951:antiglomerular basement membrane antibody; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine