A1 adenosine receptor knockout mice exhibit increased renal injury following ischemia and reperfusion

Am J Physiol Renal Physiol. 2004 Feb;286(2):F298-306. doi: 10.1152/ajprenal.00185.2003. Epub 2003 Nov 4.

Abstract

Controversy exists regarding the effect of A1 adenosine receptor (AR) activation in the kidney during ischemia and reperfusion (I/R) injury. We sought to further characterize the role of A1 ARs in modulating renal function after I/R renal injury using both pharmacological and gene deletion approaches in mice. A1 AR knockout mice (A1KO) or their wild-type littermate controls (A1WT) were subjected to 30 min of renal ischemia. Some A1WT mice were subjected to 30 min of renal ischemia with or without pretreatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) or 2-chrolo-cyclopentyladenosine (CCPA), selective A1 AR antagonist and agonist, respectively. Plasma creatinine and renal histology were compared 24 h after renal injury. A1KO mice exhibited significantly higher creatinines and worsened renal histology compared with A1WT controls following renal I/R injury. A1WT mice pretreated with the A1 AR antagonist or agonist demonstrated significantly worsened or improved renal function, respectively, after I/R injury. In addition, A1WT mice pretreated with DPCPX or CCPA showed significantly increased or reduced markers of renal inflammation, respectively (renal myeloperoxidase activity, renal tubular neutrophil infiltration, ICAM-1, TNF-alpha, and IL-1beta mRNA expression), while demonstrating no differences in indicators of apoptosis. In conclusion, we demonstrate that endogenous or exogenous preischemic activation of A1 ARs protects against renal I/R injury in vivo via mechanisms leading to decreased necrosis and inflammation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acute Kidney Injury / immunology
  • Acute Kidney Injury / mortality
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / physiopathology*
  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacology
  • Adenosine A1 Receptor Antagonists
  • Animals
  • Apoptosis
  • Biomarkers
  • Genotype
  • In Situ Nick-End Labeling
  • Intercellular Adhesion Molecule-1 / genetics
  • Interleukin-1 / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Necrosis
  • Neutrophils / pathology
  • RNA, Messenger / analysis
  • Receptor, Adenosine A1 / genetics*
  • Reperfusion Injury / immunology
  • Reperfusion Injury / mortality
  • Reperfusion Injury / pathology
  • Reperfusion Injury / physiopathology*
  • Tumor Necrosis Factor-alpha / genetics
  • Xanthines / pharmacology

Substances

  • Adenosine A1 Receptor Antagonists
  • Biomarkers
  • Interleukin-1
  • RNA, Messenger
  • Receptor, Adenosine A1
  • Tumor Necrosis Factor-alpha
  • Xanthines
  • Intercellular Adhesion Molecule-1
  • 2-chloro-N(6)cyclopentyladenosine
  • 1,3-dipropyl-8-cyclopentylxanthine
  • Adenosine