Kidney Week

Abstract: FR-PO270

The Transcriptional Regulator AP-2α Maintains the Tubular Diameter of Renal Collecting Ducts in Adult Mice

Session Information

• Genetic Diseases of the Kidneys: Cystic - II
  November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1101 Genetic Diseases of the Kidneys: Cystic

Authors

• Leiz, Janna, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Janna Leiz,

• Cao, Shuang, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany

Shuang Cao,

• Boivin, Felix, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Felix Boivin,

• Hinze, Christian, Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany

Christian Hinze,

• Schmidt-Ott, Kai M., Medizinische Hochschule Hannover, Hannover, Niedersachsen, Germany

Kai M. Schmidt-Ott,

Group or Team Name

• Molecular and Translational Kidney Research

Background

The transcriptional regulator AP-2α, encoded by the Tfap2a gene, is part of the AP-2 transcription factor family. Heterozygous missense mutations of TFAP2A in humans result in branchio-oculo-facial syndrome (BOFS), which is associated with renal anomalies in about 35 % of patients. Recent studies demonstrated that mice with a collecting duct-specific knockout of AP-2α display a progressive tubular dilation of medullary collecting ducts. Molecular mechanisms resulting in these renal anomalies are still unknown.

Methods

Mice carrying a collecting duct-specific knockout of AP-2α (Hoxb7:Tfap2a^fl/fl) were generated. In addition, inner medullary collecting duct (IMCD3) cells were engineered to harbour a CRISPR/Cas9-induced knock out of AP-2α. Deregulated genes were identified by bulk and single-nucleus mRNA-sequencing and validated by in situ hybridization.

Results

Histomorphological analyses of our mouse model confirmed a progressive tubular dilation of outer medullary collecting ducts in adult mice over a period of six month. Integrative analysis of single-nucleus and bulk RNA-sequencing for kidneys of 3-months-old Hoxb7:Tfap2a^fl/fl mice and littermate controls indicated deregulated expression of genes associated with cell adhesion and WNT signaling pathways. Identical pathways were deregulated in AP-2α-deficient IMCD3 cells when compared to controls. Genes deregulated in AP-2α -deficient collecting ducts included the tight junction component Cldn8 and the Wnt signaling factor Wnt9b. Their decreased mRNA expression was confirmed by in-situ hybridization. Both genes have previously been implicated in the development of renal anomalies and defects in tubulogenesis.

Conclusion

Taken together our study indicates that AP-2α is essential for the maintenance of tubular diameter and epithelial differentiation in collecting ducts of adult mice, providing insights into potential molecular mechanisms causing renal defects observed in BOFS.