Interferon Regulatory Factor-5 in Resident Macrophage Promotes Polycystic Kidney Disease.

Academic Article

Abstract

  • BACKGROUND: Autosomal dominant polycystic kidney disease is caused by genetic mutations in PKD1 or PKD2. Macrophages and their associated inflammatory cytokines promote cyst progression; however, transcription factors within macrophages that control cytokine production and cystic disease are unknown. METHODS: In these studies, we used conditional Pkd1 mice to test the hypothesis that macrophage-localized interferon regulatory factor-5 (IRF5), a transcription factor associated with production of cyst-promoting cytokines (TNF╬▒, IL-6), is required for accelerated cyst progression in a unilateral nephrectomy (1K) model. Analyses of quantitative real-time PCR (qRT-PCR) and flow-cytometry data 3 weeks post nephrectomy, a time point before the onset of severe cystogenesis, indicate an accumulation of inflammatory infiltrating and resident macrophages in 1K Pkd1 mice compared with controls. qRT-PCR data from FACS cells at this time demonstrate that macrophages from 1K Pkd1 mice have increased expression of Irf5 compared with controls. To determine the importance of macrophage-localized Irf5 in cyst progression, we injected scrambled or IRF5 antisense oligonucleotide (ASO) in 1K Pkd1 mice and analyzed the effect on macrophage numbers, cytokine production, and renal cystogenesis 6 weeks post nephrectomy. RESULTS: Analyses of qRT-PCR and IRF5 ASO treatment significantly reduced macrophage numbers, Irf5 expression in resident-but not infiltrating-macrophages, and the severity of cystic disease. In addition, IRF5 ASO treatment in 1K Pkd1 mice reduced Il6 expression in resident macrophages, which was correlated with reduced STAT3 phosphorylation and downstream p-STAT3 target gene expression. CONCLUSIONS: These data suggest that Irf5 promotes inflammatory cytokine production in resident macrophages resulting in accelerated cystogenesis.
  • Keywords

  • Animals, Interferon Regulatory Factors, Kidney, Macrophages, Mice, Polycystic Kidney Diseases, Polycystic Kidney, Autosomal Dominant
  • Digital Object Identifier (doi)

    Author List

  • Zimmerman KA; Huang J; He L; Revell DZ; Li Z; Hsu J-S; Fitzgibbon WR; Hazard ES; Hardiman G; Mrug M
  • Start Page

  • 179
  • End Page

  • 190
  • Volume

  • 1
  • Issue

  • 3