Abstract: SA-PO458
Interferon Regulatory Factor 5 Expressed in Kidney Resident Macrophages Promotes Polycystic Kidney Disease
Session Information
- Cystic Kidney Diseases: Basic/Translational
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Zimmerman, Kurt, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Huang, Jifeng, University of Alabama at Birmingham, Birmingham, Alabama, United States
- He, Lan, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Revell, Dustin Z., University of Alabama at Birmingham, Birmingham, Alabama, United States
- Li, Zhang, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Fitzgibbon, Wayne R., Medical University of South Carolina, Charleston, South Carolina, United States
- Hazard, Edward S., Medical University of South Carolina, Charleston, South Carolina, United States
- Hardiman, Gary, Queen's University Belfast, Belfast, United Kingdom
- Mrug, Michal, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Bell, Phillip Darwin, University of Alabama at Birmingham, Birmingham, Alabama, United States
- Yoder, Bradley K., University of Alabama at Birmingham, Birmingham, Alabama, United States
- Saigusa, Takamitsu, University of Alabama at Birmingham, Birmingham, Alabama, United States
Background
Autosomal dominant polycystic kidney disease (ADPKD) is caused by genetic mutations in Pkd1 or Pkd2. Previous data indicate that pro-inflammatory cytokines including TNFα, IL-6, and MCP1, as well as their downstream signaling components, are associated with macrophages and accelerated cystogenesis. Recent data indicate that the Irf5 transcription factor promotes a pro-inflammatory macrophage phenotype.
Methods
In these studies, we assess the importance of macrophage-derived Irf5 during accelerated cystogenesis induced by unilateral nephrectomy (1K) in conditional Pkd1 mice.
Results
Analyses of RNA sequencing, qRT-PCR, and flow cytometry data from whole kidney tissue collected three weeks post nephrectomy, a time point prior to the onset of severe cystogenesis, indicate an enriched inflammatory macrophage signature, including increased Irf5 expression, in 1K Pkd1 mice compared to controls. To determine the importance of Irf5 in cyst progression, we injected scrambled or IRF5 antisense oligonucleotide (ASO) in 1K Pkd1 mice and analyzed the effect on cytokine production and renal cystogenesis 6 weeks post nephrectomy. Our data indicate that IRF5 ASO treatment significantly reduced macrophage numbers, Irf5 expression in resident, but not infiltrating, macrophages, and reduced the severity of cystic disease. In addition, IRF5 ASO treatment reduced the expression of the pro-inflammatory cytokine Il6 in resident macrophages, which correlated with reduced STAT3 phosphorylation and downstream p-STAT3 target gene expression in 1K Pkd1 mice.
Conclusion
These data indicate that Irf5 expressed in resident macrophages promotes accelerated cystogenesis.
Funding
- NIDDK Support