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

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 A1 adenosine receptors (huA1AR) 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-huA1AR. 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-huA1AR 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-huA1AR lentivirus-injected kidney before hepatic ischemia abolished both renal and hepatic protection after liver IR showing that the overexpression of huA1AR 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 A1ARs in the kidney leads to protection of both liver and kidney after hepatic IR.