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Kidney Week

Abstract: TH-PO085

Prerenal Azotemia Triggers the Hepatic Acute Response in a Novel, Clinically Defined Murine Model

Session Information

  • AKI: Mechanisms - I
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Okamura, Kayo, University of Colorado, Denver, Colorado, United States
  • Lu, Sizhao, University of Colorado, Denver, Colorado, United States
  • He, Zhibin, University of Colorado, Denver, Colorado, United States
  • Montford, John R., University of Colorado, Denver, Colorado, United States
  • Weiser-evans, Mary C.M., University of Colorado, Denver, Colorado, United States
  • Faubel, Sarah, University of Colorado, Denver, Colorado, United States
Background

Prerenal azotemia (PRA) is uncommonly studied in murine models and is thought to be systemically inert. We developed a novel murine model of PRA that met the current clinical definition in humans: Decreased GFR that returns to baseline with restoration of hemodynamics. Since plasma IL-6 is elevated during AKI, in part due to reduced GFR and is the major mediator of the hepatic acute phase response, we hypothesized that PRA would result in elevated plasma levels of IL-6 and hepatic production of acute phase proteins.

Methods

Mice: C57Bl/6J. Interventions: 4 mg of furosemide IP (PRA) or vehicle (Veh) at time 0 hours and 3 hours in wild type (WT) and IL-6 -/- mice; at 6 hours, resuscitation was started with 1 mL IP saline x 4 over 36 hours. Measurements: transdermal measured glomerular filtration rate (tGFR) at baseline, 6 and 48 hours; all other measurements at 6 hours that included: plasma IL-6, NGAL, CXCL1, and haptoglobin, and hepatic tissue RNAseq.

Results

tGFR was 30% of normal at 6 hours and returned to baseline at 48 hours. At 6 hours, plasma IL-6 was significantly increased, renal and liver histology were normal, renal and liver lactate were normal, and renal KIM-1 IF was normal. By RNAseq, 587 differentially regulated genes were significantly changed in the liver in WT PRA versus WT Veh; 327 genes were significantly upregulated and 260 were significantly suppressed; the acute phase response was the most significantly upregulated pathway. 25% of upregulated genes in the liver were reduced in IL-6 -/- PRA, and the acute phase response was the most significantly downregulated pathway. Hepatic gene expression and protein levels were determined for 3 of the significantly upregulated genes: NGAL, CXCL1, and haptoglobin; gene expression and plasma protein levels were all increased in WT PRA versus WT Veh and were all reduced in IL-6 -/- PRA versus WT PRA.

Conclusion

These data demonstrate previously unknown systemic effects of PRA, demonstrating that significant consequences may occur with the sudden loss of GFR in the absence of tubular injury. Since it is widely thought that the systemic consequences of AKI are predominantly associated with tubular injury, these data change the paradigm by which the consequences of PRA should be be considered.