Description
Prerenal azotemia (PRA) is a major cause of acute kidney injury (AKI) and uncommonly studied in preclinical models. Using a reverse translational approach, we developed a novel model of PRA that meets the clinical definition. 6 hours after furosemide administration to induce volume loss in wild type (WT) mice, 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 reduced in IL-6-/-, and the acute phase response was the most significantly downregulated pathway. Three significantly upregulated genes were further investigated: NGAL, 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 systemic inflammation and IL-6 mediated upregulation of the hepatic acute phase response; we anticipate that these effects will have significant clinical consequences.
Overall Design
Using RNA-seq to profile the transcriptomes of hepatic tissues in wild type (WT) and IL-6-/- mice subjected to vehicle (Veh, 4 WT replicates, 4 IL-6-/- replicates) or furosemide-induced pre-renal azotemia (PRA, 4 WT replicates, 3 IL-6-/- replicates) treatments. Non-injected mice (normal, 4 replicates) were used examined as control.
Curator
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