Renal Dysfunction in the Setting of Massive Hepatic Necrosis: A Network-based Analysis in a Mouse

To date, no published reports (human or animal) have examined the impact of acute liver failure on global gene expression profiles in remote organ systems like the kidney. In this study, we have characterized a model of acute kidney injury (AKI) using two highly-accurate techniques for assessing renal function in a mouse. In this model, mice developed massive hepatocyte necrosis, disordered hepatosplanchnic hemodynamics, and alterations consistent with ALF. Simultaneously, acute renal insufficiency developed, manifesting as oliguria, azotemia, and decreased glomerular filtration. In this paper, renal function is corroborated using two independent methodologies. These techniques are used in addition to hemodynamic, biochemical, and histologic analyses to demonstrate that acute hepatic injury promulgates renal dysfunction in a mouse. Similar to network-based analyses conducted in other models of human disease, we present a comprehensive, genome-wide assessment of the differentially-regulated, renal transcriptome in the setting of massive hepatic necrosis. Using this approach, mice receiving the select hepatotoxin D-(+)-Galactosamine HCl (GalN) were found to have significant perturbations in renal pathways related to lipid metabolism, small molecule biochemistry, the cell cycle, molecular transport, and amino acid metabolism, despite normal renal histology. By combining data obtained from clinical, physiologic, and molecular investigations, our findings have direct implications for exploring potential pharmacological approaches to the prevention of AKI in this setting.

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