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Abstract: PO1238

FoxM1 Promotes Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Yu, Wenyan, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Wang, Guojuan, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Li, Xiaoyan, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Zhou, Xia, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
  • Li, Xiaogang, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in PKD1 and PKD2 genes and is characterized by renal cyst formation, inflammation and fibrosis. Forkhead box protein M1 (FoxM1) is a transcription factor of the Forkhead box (Fox) protein super family which is defined by a conserved winged helix DNA-binding domain 1. FoxM1 has been reported to promote tumor formation, inflammation and fibrosis in many organs. However, the role and mechanism of FoxM1 in regulation of ADPKD progression is still poorly understood.

Methods

To evaluate the role and mechanisms of FoxM1 in cyst growth in vivo, we treated early stage and long lasting Pkd1 mutant mice with the FoxM1 specific inhibitor, FDI-6. To identify novel FoxM1 target genes involved in cystogenesis, we performed ChIP-sequencing analysis.

Results

We found that FoxM1 was upregulated in cyst-lining epithelial cells in polycystin-1-deficient murine kidneys and human ADPKD kidneys. Inhibition of FoxM1 with FDI-6 delayed cyst growth as seen by decreased cystic index, kidney weight (KW)/body weight (BW) ratios, blood urea nitrogen (BUN) levels, cyst lining epithelial cell proliferation, and increased cyst lining epithelial cell apoptosis in Pkd1 mutant mice (all p < 0.01). Targeting FoxM1 also decreased renal fibrosis in long last Pkd1 mutant kidneys. Upregulation of FoxM1 promotes cyst growth through: 1) upregulation of the expression of Akt and Stat3 and activation of ERK and Rb signaling to increase cystic renal epithelial cell proliferation, 2) inhibition of p65-dependent cystic renal epithelial cell death, 3) facilitation of the recruitment and retention of renal macrophages, and 4) upregulation and activation of fibrotic markers to promote renal fibrosis. In addition, FoxM1-dependent macrophage recruitment was associated with upregulation of monocyte chemotactic protein 1 (MCP-1) and inflammatory cytokine TNF-α. Further, we identified novel FoxM1 target genes by ChIP-seq analysis, which may connect FoxM1 signaling to the ciliopathy hypothesis in PKD.

Conclusion

FoxM1 promotes renal cyst growth and fibrosis in ADPKD through Akt, ERK, Rb and STAT3 signaling as well as NF-kB and ciliopathy associated signaling. Targeting FoxM1 in cystic renal epithelial cells may be a viable new therapy for ADPKD.

Funding

  • NIDDK Support