Abstract: TH-PO587

Suppressing Interferon Regulatory Factor-5 Synthesis Attenuates Kidney Macrophages and Cytokines in Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases

Authors

  • Zimmerman, Kurt, University of Alabama at Birmingham , Birmingham, Alabama, United States
  • He, Lan, University of Alabama at Birmingham , Birmingham, Alabama, United States
  • Yoder, Bradley K., University of Alabama at Birmingham , Birmingham, Alabama, United States
  • Revenko, Alexey, Ionis Pharmaceuticals, Carlsbad, California, United States
  • Mullick, Adam E., Ionis Pharmaceuticals, Carlsbad, California, United States
  • Bell, P. Darwin, University of Alabama at Birmingham , Birmingham, Alabama, United States
  • Saigusa, Takamitsu, University of Alabama at Birmingham , Birmingham, Alabama, United States
Background

Inflammatory cells are increased in both human and mouse models of polycystic kidney diseases (PKD). Interestingly, macrophages in the kidney may appear before significant cystic development and deleting phagocytic macrophages with liposomal clodronate has been reported to slow cyst formation. Interferon regulatory factor-5 (IRF5) is a transcription factor involved in activation of macrophage and cytokine release and maybe an effective target for therapeutic intervention. To determine the significance of IRF5 and macrophages in PKD, we tested an antisense oligonucleotide (ASO) that inhibits IRF5 in adult Pkd1 mice.

Methods

Four week old adult Pkd1 conditional floxed allele mice with or without cre were administered tamoxifen to induce cre. Two weeks after tamoxifen injection, mice underwent unilateral nephrectomy to accelerate cyst formation. After nephrectomy, mice were treated with weekly injection of either IRF5 ASO (40mg/kg/wk) or scrambled ASO for a total of 3 weeks. Kidneys were harvested for analysis at the end of the treatment.

Results

Three weeks following nephrectomy, Pkd1-/- mice showed early focal cyst formation/dilated tubules in the kidney. Pkd1-/-mice treated with IRF5 ASO demonstrated significant reduction in level of kidney IRF5 mRNA compared to scrambled ASO treatment. Flow cytometry analysis of kidneys suggest that treatment with IRF5 ASO specifically reduces the number of infiltrating and resident macrophages but the level of neutrophils and T cells was unaffected by IRF5 ASO. IRF5 ASO compared to control ASO reduced kidney mRNA levels of pro-inflammatory cytokines.

Conclusion

These results suggest that suppressing IRF5 reduced both resident and infiltrating macrophages in early stage of PKD and may potentially become a novel therapeutic target in PKD.

Funding

  • NIDDK Support