Kidney Week

Abstract: PO1211

The Transcription Factor Tfap2a Maintains the Epithelial Integrity of Renal Collecting Ducts

Session Information

• Cystic Kidney Disease - I
  November 04, 2021 | Location: On-Demand, Virtual Only
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

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

Janna Leiz

• Hinze, Christian, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Christian Hinze,

• Schmidt-Ott, Kai M., Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany

Kai M. Schmidt-Ott,

Background

The transcriptional regulator Tfap2a is a member of the AP-2 family of transcription factors. In humans, heterozygous mutations of Tfap2a result in branchio-oculo-facial syndrome (BOFS), which is associated with renal anomalies, including dysplastic, absent and multicystic kidneys. In this project, we aimed to elucidate the molecular functions of Tfap2a in the renal collecting duct.

Methods

We generated mice carrying a collecting duct-specific knockout of Tfap2a (Tfap2a^CD-/-) by crossing Hoxb7;Cre and Tfap2a^flox/flox mice. Newborn and adult mice were analyzed using histology, in situ hybridization, bulk RNA sequencing and single nucleus RNA sequencing.

Results

Tfap2a was expressed in the ureteric bud and distal region of the S-shaped body in kidneys of newborn wildtype mice and expression was maintained in mature distal tubules and collecting ducts. Tfap2a^CD-/- mice displayed moderately reduced kidney weights (20 % reduction compared to controls) and a progressive dilation of outer medullary collecting ducts throughout six months of life. Bulk and single nuclei RNA sequencing of kidneys of three months old Tfap2a^CD-/- mice and littermate controls indicated deregulated expression of genes associated with cellular adhesion and epithelial integrity, such as Cldn8 and Npnt. In addition, Wnt9b, a factor previously described as a regulator of planar cell polarity and tubule diameter, was downregulated in collecting ducts of Tfap2a^CD-/- mice.

Conclusion

Our data indicate that the transcription factor Tfap2a regulates kidney size and contributes to the continued integrity of the collecting duct epithelium. Our data provide insights into potential molecular mechanisms underlying renal defects observed in BOFS.