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Kidney Week

Abstract: PO0203

Renal Angiotensin (Ang) Receptor Changes Following Cecal Ligation and Puncture (CLP)-Induced AKI

Session Information

  • AKI Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Lehman, Jake R., Northwell Health Feinstein Institutes for Medical Research, Manhasset, New York, United States
  • Leisman, Daniel E., Northwell Health Feinstein Institutes for Medical Research, Manhasset, New York, United States
  • Fernandes, Tiago, Northwell Health Feinstein Institutes for Medical Research, Manhasset, New York, United States
  • Taylor, Matthew D., Northwell Health Feinstein Institutes for Medical Research, Manhasset, New York, United States
  • Brewer, Mariana Rae, Northwell Health Feinstein Institutes for Medical Research, Manhasset, New York, United States
  • Abraham, Mabel N., Northwell Health Feinstein Institutes for Medical Research, Manhasset, New York, United States
  • Deutschman, Clifford S., Northwell Health Feinstein Institutes for Medical Research, Manhasset, New York, United States
Background

Angiotensin-II (Ang2) modulates renal function and thus may contribute to sepsis-induced acute kidney injury (SIAKI). We have shown that CLP reduced renal Ang2 type-1 receptors (AT1R), but effects on non-classical Ang receptors are unknown. We hypothesized that CLP altered renal abundance of Ang2 type-2 receptors (AT2R) and Ang(1-7), Mas receptors (Ang(1-7)R, MasR), initiators of signaling axes that oppose AT1R.

Methods

C57BL6 mice were randomized to euthanasia at 6, 24, or 48hrs post-CLP (n=5/group). Unoperated mice (T0) served as controls. Mice were resuscitated (50mL/kg NS SQ) immediately and 25 hrs post-operatively. Prior to sacrifice we removed the kidneys under deep isoflurane anesthesia to minimize tissue ischemia. We obtained blood by cardiac puncture. Kidney Injury Molecule-1 (KIM-1) was measured in whole tissue homogenate (ELISA). AT1R, AT2R, and MasR were measured within specific regions of the kidney using immunofluorescence, (IF). We also used IF to compare kidney sections collected from sepsis patients within an hour of death (n=7) to sections from healthy controls (n=10).

Results

KIM-1 and BUN increased 6h post-CLP. Creatinine increased 48h post-CLP. We have previously shown that CLP reduced AT1R in arterioles, macula densa, and glomeruli. However, CLP did not alter MasR abundance in any region (p>0.05). The ratio of total renal MasR to AT1R more than doubled by 6hrs post-CLP (p<0.001 vs. T0). Renal AT2R intensity was increased in renal mesangium by 24h and in glomeruli by 48h (p<0.01 for both). We previously showed decreased AT1R IF in human sepsis kidney sections. In contrast, human sepsis kidneys did not show any decrease in MasR (p>0.05), again suggesting an increase in the MasR to AT1R ratio.

Conclusion

1. Data on CLP-induced changes in KIM-1 in tissue and BUN in blood suggest that these are earlier markers of CLP-induced renal injury than serum creatinine.
2. CLP and septic AKI may be associated with a shift from classical to non-classical angiotensin signaling in the kidney. Studies of non-classical angiotensin system modulation in septic AKI may enhance understanding of pathobiology and reveal therapeutic targets in septic AKI.