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Abstract: PO1397

Tfap2a Integrates Cellular Patterning and Barrier Formation in the Renal Collecting Duct

Session Information

Category: Fluid, Electrolyte, and Acid-Base Disorders

  • 901 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

  • Leiz, Janna, Department of Nephrology and Intensive Care, Charite - Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Hinze, Christian, Department of Nephrology and Intensive Care, Charite - Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Schmidt-Ott, Kai M., Department of Nephrology and Intensive Care, Charite - Universitatsmedizin Berlin, Berlin, Berlin, Germany
Background

The renal collecting duct plays important roles in fine-tuning urinary composition, electrolyte and water balance, blood pressure, as well as acid-base regulation. The patterning and molecular signatures of principal cells (PCs) and intercalated cells (ICs) of the collecting duct are tightly controlled by transcriptional processes and determine collecting duct physiological function and related clinical abnormalities. The transcription factor Tfap2a has previously been implicated in epithelial differentiation, in pronephros development in zebrafish, and in human congenital kidney defects. Using an integrated bioinformatics approach, we predicted that Tfap2a may critically control collecting duct functions. We tested our hypothesis using experimental model systems.

Methods

A collecting duct-specific knockout of Tfap2a was generated in mice. Additionally, mouse inner medullary collecting duct (IMCD3) cells were engineered to harbor CRISPR/Cas9-induced knockouts (KO) of Tfap2a. Deregulated genes were identified by mRNA sequencing. Patterns of principal and intercalated cells in mouse kidneys were analyzed by microscopy. Additionally, the in vivo model was used in metabolic studies to analyze urinary concentration ability.

Results

Mice lacking Tfap2a in the collecting duct were viable and fertile but showed a defect of urinary concentrating ability. mRNA sequencing of Tfap2a-deficient kidneys and cells and subsequent gene ontology analysis indicated an impact of Tfap2a on molecular processes including Notch signaling, focal adhesion formation and tight junction formation. Further experiments indicated abnormalities of PC/IC patterning in Tfap2a-deficient collecting ducts.

Conclusion

Our data suggest that Tfap2a controls transcriptional processes that integrate patterning and barrier formation in the collecting duct.