Selective intrarenal human A1 adenosine receptor overexpression reduces acute liver and kidney injury after hepatic ischemia reperfusion in mice

Lab Invest. 2010 Mar;90(3):476-95. doi: 10.1038/labinvest.2009.143. Epub 2010 Jan 11.

Abstract

Acute kidney injury (AKI) is frequent after liver ischemia reperfusion (IR) can potentiate liver injury and is often complicated by subsequent multiorgan dysfunction syndrome. AKI because of liver IR is characterized by early renal endothelial cell apoptosis and impaired vascular integrity with subsequent neutrophil infiltration, proximal tubule necrosis/inflammation, and filamentous (F) actin disintegration. We tested whether selective renal overexpression of human A(1) adenosine receptors (huA(1)AR) protects against both liver and kidney injury sustained after liver IR. Mice were subjected to liver IR or to sham surgery 48 h after unilateral intrarenal injection of lentivirus encoding enhanced green fluorescent protein (EGFP) or EGFP-huA(1)AR. Intrarenal lentiviral gene delivery caused a robust transgene expression in the injected kidney without significant expression in the contralateral kidney or in the liver. Mice injected with EGFP-huA(1)AR lentivirus were protected against hepatic IR-induced liver and kidney injury with reduced necrosis, inflammation, and apoptosis, and better preserved F-actin and vascular permeability compared with mice injected with EGFP lentivirus. Importantly, we show that removing the EGFP-huA(1)AR lentivirus-injected kidney before hepatic ischemia abolished both renal and hepatic protection after liver IR showing that the overexpression of huA(1)AR in the injected kidney has a crucial role in protecting the kidney and liver after liver IR. Therefore, our findings show that protecting the kidney reduces liver IR injury and selective overexpression of cytoprotective A(1)ARs in the kidney leads to protection of both liver and kidney after hepatic IR.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / prevention & control*
  • Animals
  • Apoptosis
  • Capillary Permeability
  • Chemokine CCL2 / blood
  • Genetic Therapy*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HSP27 Heat-Shock Proteins / metabolism*
  • Humans
  • Injections
  • Intercellular Adhesion Molecule-1 / blood
  • Kidney / immunology
  • Kidney / metabolism
  • Kidney / pathology
  • Lentivirus
  • Liver / metabolism
  • Liver / pathology
  • Liver Failure, Acute / pathology
  • Liver Failure, Acute / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Necrosis
  • Neutrophil Infiltration
  • Receptor, Adenosine A1 / genetics
  • Receptor, Adenosine A1 / metabolism*
  • Reperfusion Injury / prevention & control*
  • Tumor Necrosis Factor-alpha / blood
  • Up-Regulation

Substances

  • Actins
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • HSP27 Heat-Shock Proteins
  • Hspb2 protein, mouse
  • Receptor, Adenosine A1
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • Green Fluorescent Proteins