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Kidney Week

Abstract: FR-PO968

Collecting Duct-Specific Deletion of the Transcription Factor Grainyhead-Like 2 (Grhl2) Aggravates Cyst Growth in Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic

Authors

  • Yurtdas, Zeliha Yesim, Berlin Institute for Urologic Research, Berlin, Germany
  • Kilic, Ergin, Institut für Pathologie am Klinikum Leverkusen, Leverkusen, Germany
  • Wyler, Emanuel, Max Delbrück Center for Molecular Medicine, Berlin, Germany
  • Boor, Peter, RWTH University Aachen, Aachen, Germany
  • Schmidt-Ott, Kai M., Charite - Universitaetsmedizin Berlin, Berlin, Germany
Background

Polycystic kidney disease (PKD) is a genetic disorder characterized by the development of cysts as a result of abnormalities in proliferation, apoptosis and dedifferentiation of the renal epithelium. The transcription factor Grhl2 is highly expressed in the collecting duct cells of the kidney and controls epithelial barrier function in the mouse kidney. The collecting duct is known to be an important source of cysts in PKD, but whether Grhl2 is involved in cyst formation and growth is not known.

Methods

To investigate the role of Grhl2 in PKD pathogenesis, we first examined GRHL2 protein expression in kidney samples from patients with autosomal dominant PKD (ADPKD). We then studied the effects of a collecting duct-specific Grhl2 deletion on a mouse model with slowly progressive PKD caused by overexpression of the human MYC proto-oncogene. We compared renal phenotypes of HoxB7-Cre; R26StopFLMYC; Grhl2flox/flox mice and HoxB7Cre; R26StopFLMYC mice using functional, histological assays and gene expression profiling.

Results

Analyses of patient samples with ADPKD (n=6) revealed that GRHL2 protein was downregulated by 65% in collecting duct-derived cyst-lining epithelia when compared with its expression in healthy collecting ducts (n=4). HoxB7Cre; R26StopFLMYC mice developed slowly progressive bilateral polycystic kidneys that mimicked human ADPKD. Collecting duct-specific deletion of Grhl2 in the kidneys of HoxB7Cre, R26StopFLMYC mice (HoxB7-Cre; R26StopFLMYC; Grhl2flox/flox) markedly accelerated PKD progression, led to a more aggressive bilateral cystic kidney disease, and caused early lethality. Proliferation and apoptosis rates of cyst-lining epithelia were found to be significantly higher in HoxB7Cre; R26StopFLMYC; Grhl2 flox/flox mice compared with HoxB7Cre; R26StopFLMYC mice. Furthermore, a genome-wide analysis of differentially regulated genes in HoxB7Cre; R26StopFLMYC; Grhl2 flox/flox mice compared with HoxB7-Cre; R26StopFLMYC mice identified deregulation of genes involved in cell-cycle regulation and epithelial cell polarity.

Conclusion

Our data indicate a role for Grhl2 and its target gene program in the progression of collecting duct-derived cyst formation in PKD. Targeting Grhl2 activity may constitute a novel strategy to limit cyst progression.

Funding

  • Private Foundation Support