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Kidney Week

Abstract: FR-PO737

Vascular Disease in PKD: A Novel Role for MLL1 in the Hedgehog-GLI1 Regulated Pro-Angiogenic Genes in Endothelial Cells

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Franchi, Federico, Mayo Clinic, Rochester, Minnesota, United States
  • Peterson, Karen M., Mayo Clinic, Rochester, Minnesota, United States
  • Tolosa, Ezequiel J., Mayo Clinic, Rochester, Minnesota, United States
  • Harris, Peter C., Mayo Clinic, Rochester, Minnesota, United States
  • Fernandez-Zapico, Martin E., Mayo Clinic, Rochester, Minnesota, United States
  • Rodriguez- Porcel, Martin G., Mayo Clinic, Rochester, Minnesota, United States
Background

We have previously reported that activation of the Hedgehog (Hh) pathway is severely impaired in Polycystic Kidney Disease Endothelial Cells (PKD-ECs), leading to endothelial dysfunction and development of vascular defects. Furthermore, the severity of vascular dysfunction cannot be completely accounted for by the genetic defects, suggesting that other factors play a role. Here, we hypothesized that epigenetic changes modulating PKD-ECs transcriptome are responsible for the abnormal endothelial phenotype.

Methods

We studied the expression and regulation of pro-angiogenic molecules, such as vascular endothelial growth factor A (VEGFA), Angiopoietin 1 (ANG1) and Angiopoietin 2 (ANG2) using Chromatin Immunoprecipitation (ChIP) and gene expression assays in ECs stimulated with Smoothened Agonist (SAG, 100 nM for 24 hrs).

Results

ChIP studies demonstrated that VEGFA, ANG1 and ANG2 are direct targets of the transcription factor GLI1, after activation of the Hh pathway. Furthermore, PKD-ECs displayed lower binding of GLI1 (Fig. 1A) and histone methyltransferase MLL1 (Fig. 1B) to the promoter region of those pro-angiogenic genes, compared to WT-ECs. Importantly, analysis of Histone 3 Lysine 4 methylation revealed a lower enrichment of methyl groups in PKD-ECs compared to WT (Fig. 1C).

Conclusion

Our data suggest that there is a specific epigenetic pathway affected in PKD controlling the ECs phenotype. These studies provide the base for the development of novel therapeutic strategies that, through modulation of epigenetic mechanisms, focus on the vascular aspects of PKD.

Funding

  • NIDDK Support