A2A adenosine receptor agonist and PDE4 inhibition delays inflammation but fails to reduce injury in experimental obstructive nephropathy.
BACKGROUND
Renal interstitial inflammation is a consequence of unilateral ureteral obstruction (UUO). Following ischemia/reperfusion, adenosine reduces renal inflammation and injury, effects which are potentiated by type 4 phosphodiesterase inhibitors. We therefore studied the effects of A2A adenosine receptor agonist (ATL146e), and PDE4 inhibitor (rolipram) in mice subjected to UUO.


METHODS
Mice were subjected to UUO or sham operation, and received either vehicle or ATL146e + rolipram by osmotic minipump for 1 or 7 days. At 1, 3, 7, or 14 days after operation, renal macrophage infiltration, apoptosis, proliferation, tubular atrophy, and interstitial fibrosis were quantitated, and expressions of IL-6 and TGF-beta mRNA were determined.


RESULTS
ATL146e + rolipram reduced macrophage infiltration by 40% after 3 days UUO (p < 0.05). Tubular apoptosis, tubular atrophy, and interstitial fibrosis were increased by 7 or 14 days UUO, but were unaffected by ATL146e + rolipram. However, cellular proliferation was increased by ATL146e + rolipram in the obstructed kidney. ATL146e + rolipram had no effect on the renal expression of IL-6 and TGF-beta mRNA.


CONCLUSIONS
A2A receptor activation and PDE4 inhibition transiently reduce renal macrophage infiltration, but do not ameliorate the renal response to UUO. We speculate that the persistent stimulus for inflammation triggered by UUO cannot be reversed by agents that suppress inflammatory cell activation alone.
Lange-Sperandio
Bärbel
B
Department of Pediatrics, Ruprecht Karls University, Heidelberg, Germany.
Forbes
Michael S
MS
Thornhill
Barbara
B
Okusa
Mark D
MD
Linden
Joel
J
Chevalier
Robert L
RL
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D005355:Fibrosis; D007249:Inflammation / Q000503:physiopathology*; D007674:Kidney Diseases / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D043683:Receptors, Adenosine A2 / Q000187:drug effects / Q000502:physiology*; D020889:Rolipram / Q000494:pharmacology*; D014517:Ureteral Obstruction / Q000150:complications*
C431129:ATL 146e; D003509:Cyclohexanecarboxylic Acids; D010726:Phosphodiesterase Inhibitors; D011687:Purines; D043683:Receptors, Adenosine A2; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram