Kidney Week

Abstract: TH-PO678

The Role of Interferon Regulatory Factor-5 in Acceleration of Cystogenesis in Polycystic Kidney Disease

Session Information

• ADPKD: Genetic and Model Studies
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1001 Genetic Diseases of the Kidney: Cystic

Authors

• Zimmerman, Kurt, University of Alabama at Birmingham, Birmingham, Alabama, United States

Kurt Zimmerman,

• Huang, Jifeng, University of Alabama at Birmingham, Birmingham, Alabama, United States

Jifeng Huang,

• He, Lan, University of Alabama at Birmingham, Birmingham, Alabama, United States

Lan He,

• Easter, Molly, University of Alabama at Birmingham, Birmingham, Alabama, United States

Molly Easter,

• Yoder, Bradley K., University of Alabama at Birmingham, Birmingham, Alabama, United States

Bradley K. Yoder,

• Bell, P. Darwin, University of Alabama at Birmingham, Birmingham, Alabama, United States

P. Darwin Bell,

• Saigusa, Takamitsu, University of Alabama at Birmingham, Birmingham, Alabama, United States

Takamitsu Saigusa,

Background

In mouse models of polycystic kidney disease (PKD), unilateral nephrectomy (UNx: 1K) accelerates kidney cyst growth compared to non-nephrectomized (2K) mice. Analysis of RNA sequencing data revealed that 1K compared to 2K Pkd1 deficient mice have enrichment of genes associated with inflammation, phagocytosis, and macrophages. Previous studies showed that macrophages promote cystogenesis in mouse models of PKD; however, transcription factors that control cytokine production by macrophages in cystic disease have not been identified. Herein, we study the role of interferon regulatory factor-5 (IRF5), a transcription factor involved in macrophage activation and cytokine release, during cyst progression in 2K vs 1K Pkd1 deficient mice.

Methods

Adult Pkd1^flox/flox mice with or without CAGG-cre were administered tamoxifen for global knockout of the Pkd1 gene. Three weeks after cre induction, mice underwent sham surgery or UNx to accelerate cyst formation. Kidneys were harvested at 3 (early stage) or 6 (late stage) weeks after UNx and kidney immune cells were analyzed by flow cytometry. Some mice were treated with weekly injection of IRF5 antisense oligonucleotide (40mg/kg/wk: Ionis Pharma) or scrambled ASO for a total of 3 or 6 weeks after UNx and kidney was harvested for kidney immune cells/cytokine and histology.

Results

Pkd1 deficient mice had increased kidney IRF5 mRNA levels compared to control mice. 1K Pkd1 mice increased inflammatory cytokine production, cyst growth and infiltrating (CD11b^hi, F4/80^lo) and resident macrophage (CD11b^lo, F4/80 ^hi) numbers compared to 2K Pkd1 deficient mice. Preliminary results indicate that treatment with IRF5 ASO (total 3 and 6 weeks) in 1K Pkd1 mice had no effect on kidney macrophage numbers, but significantly decreased kidney T cell accumulation, inflammatory cytokine production and cyst growth. Further comparison of male and female mice shows that 1K female mice had higher kidney IRF5 levels compared to male mice and a better response to IRF5 ASO treatment.

Conclusion

UNx in Pkd1 mice increases the number of kidney macrophages, inflammatory cytokine and cyst growth. IRF5 ASO treatment suppressed kidney IRF5 levels/reduced inflammation and attenuated the acceleration of cytogenesis in Pkd1 mice.

Funding

• NIDDK Support