A3 adenosine receptor knockout mice are protected against ischemia- and myoglobinuria-induced renal failure.
A(3) adenosine receptor (AR) activation and inhibition worsen and improve, respectively, renal function after ischemia-reperfusion (I/R) injury in rats. We sought to further characterize the role of A(3) ARs in modulating renal function after either I/R or myoglobinuric renal injury. A(3) knockout mice had significantly lower plasma creatinines compared with C57 controls 24 h after I/R or myoglobinuric renal injury. C57 control mice pretreated with the A(3) AR antagonist [3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5 dicarboxylate] or agonist [0.125 mg/kg N(6)-(3-iodobenzyl)-N-methyl-5'-carbamoyladenosine (IB-MECA)] demonstrated improved or worsened renal function, respectively, after I/R or myoglobinuric renal injury. Higher doses of IB-MECA were lethal in C57 mice subjected to renal ischemia. H(1) but not H(2) histamine receptor antagonist prevented death in mice pretreated with IB-MECA before renal ischemia. Improvement in renal function was associated with significantly improved renal histology. In conclusion, preischemic A(3) AR activation (0.125 mg/kg IB-MECA) exacerbated renal I/R injury in mice. Mice lacking A(3) ARs or blocking A(3) ARs in wild-type mice resulted in significant renal protection from ischemic or myoglobinuric renal failure.
Lee
H Thomas
HT
Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA. tl128@columbia.edu
Ota-Setlik
Ayuko
A
Xu
Hua
H
D'Agati
Vivette D
VD
Jacobson
Marlene A
MA
Emala
Charles W
CW
D058186:Acute Kidney Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D005838:Genotype; D006632:Histamine / Q000097:blood; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D009212:Myoglobinuria / Q000378:metabolism* / Q000503:physiopathology; D058906:Purinergic P1 Receptor Agonists; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000187:drug effects*; D012016:Reference Values; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology / Q000633:toxicity
D058906:Purinergic P1 Receptor Agonists; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D003189:p-Methoxy-N-methylphenethylamine; D006632:Histamine; D000241:Adenosine