Abstract
Prerenal azotemia (PRA) is a major cause of acute kidney injury (AKI) and uncommonly studied in preclinical models. We sought to develop and characterize a novel model of PRA that meets the clinical definition: acute loss of GFR that returns to baseline with resuscitation. Adult male C57Bl/6J wild type (WT) and IL-6 -/- mice were studied. 4 mg of furosemide intraperitoneally (IP) or vehicle (Veh) was administered at time 0 hr and 3 hr to induce PRA from volume loss. Resuscitation began at 6 hr with 1 mL IP saline x 4 over 36 hours. Six hours after furosemide administration, measured GFR was 25% of baseline and returned to baseline after saline resuscitation at 48 hours. At 6 hours of PRA, plasma IL-6 was significantly increased, renal and liver histology were normal, renal and liver lactate were normal, and renal KIM-1 immunofluorescence was negative; 327 differentially regulated genes were upregulated in the liver and the acute phase response was the most significantly upregulated pathway; 25% of upregulated genes were suppressed in IL-6-/- mice, and the acute phase response was the most significantly suppressed pathway. Significantly upregulated genes and their proteins were also investigated and included: serum amyloid A2, serum amyloid A1, CXCL1, and haptoglobin; hepatic gene expression and plasma protein levels were all increased in WT PRA and were all reduced in IL-6-/- PRA. This work demonstrates previously unknown systemic effects of prerenal azotemia that includes IL-6-mediated upregulation of the hepatic acute phase response.
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