Abstract: TH-PO591

Gli1 Rescues the Angiogenic Potential of Polycystic Kidney Disease-Derived Endothelial Cells

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases


  • 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

We showed that Polycystic Kidney Disease (PKD)-derived Endothelial Cells (ECs) have a diminished response to the ligand-dependent activation of the Hedgehog (Hh) pathway, leading to an impaired angiogenic potential of these cells. We then hypothesized that restoring the activity of the Hh signaling by overexpressing GLI1, a central effector of this pathway, will ameliorate the vascular defects in PKD-ECs.


To assess the role of Gli1 in ECs, we knocked-down the expression of Gli1 (using siRNA) in WT-ECs and study their angiogenic profile. To restore function, we overexpressed Gli1 in PKD-ECs and measured the expression levels of pro-angiogenic markers (phenotype) and the capacity to form vascular structures (function).


A 50% decrease in Gli1 mRNA expression was associated with a decrease in vascular endothelial growth factor A (VEGFA) expression, similar to that seen in PKD-ECs (Fig. 1A). Chromatin immunoprecipitation shows that the pro-angiogenic factors VEGFA and fibroblast growth factor 2 (FGF2) are direct targets of GLI1 in ECs. The overexpression of Gli1 in PKD-ECs led to a 740-fold increase in Gli1 mRNA expression. Importantly, exogenous Gli1 substantially restored the expression levels of the pro-angiogenic molecules VEGFA, VEGF receptor 1 (FLK1) and FGF2 (Fig. 1B), as well as the ability of PKD-ECs to form angiogenic tubes (Fig. 1C).


Our data suggest that a dysregulation in Hh signaling, and particularly of GLI1, may be responsible for the abnormal angiogenic profile seen in PKD-ECs. Furthermore, we provide evidence that Gli1 overexpression rescues the vascular deficiencies in PKD. These studies can be useful for the development of novel therapeutic strategies that focus on the vascular aspects of PKD.


  • Private Foundation Support