ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: FR-PO381

Interplay Between Ppargc1a and Esrrγa Regulates Nephron Segmentation and Ciliogenesis

Session Information

Category: Development‚ Stem Cells‚ and Regenerative Medicine

  • 500 Development‚ Stem Cells‚ and Regenerative Medicine

Authors

  • Wesselman, Hannah M., University of Notre Dame, Notre Dame, Indiana, United States
  • Wingert, Rebecca A., University of Notre Dame, Notre Dame, Indiana, United States
Background

Cilia, hair-like projections that facilitate mechano- and chemo-sensing, are nearly ubiquitous in mammalian cells. Broadly speaking, ciliopathies present phenotypes in numerous tissues, including auditory, central nervous, and renal systems. Previous research has found ppar gamma coactivator 1a (ppargc1a) as an essential regulator of renal and cilia formation, and we sought to identify cooperative factors that regulate these developmental pathways. estrogen-related receptor gamma a (esrrγa) was of interest, as it interacts with Ppargc1a in regulating other tissues, and has been independently linked to decreased kidney function.

Methods

We confirmed that esrrγa independently affects nephron development in the zebrafish embryonic kidney using whole mount in situ hybridization to characterize distinct cell types. Through immunofluorescence, we quantified aberrant cilia formation, cell polarity, and cell turnover in the kidney, ear, and node. Through dual heterozygosity models, we evaluated the relationship between esrrγa and ppargc1a in cilia and nephron development. Additionally, we used ELISA and qRT-PCR to evaluate potential downstream targets of this genetic cascade.

Results

esrrγa deficient animals exhibited nephron composition defects including expanded proximal and reduced distal segments. Similarly, we detected defects in cilia formation, where ciliated basal bodies and cilia length were significantly reduced. These phenotypes were not isolated to renal cilia, and aberrant cilia were also observed in the node and ear. By modelling heterozygosity, we found that esrrγa cooperates with ppargc1a in ciliogenesis. Specifically, both of these factors work upstream of PGE2 production by regulating Cox1.

Conclusion

These data position Esrrγ as a critical component of nephron development and cilia formation where it cooperates with Ppargc1a to modulate prostaglandin signaling. These novel findings may have clinical relevance for understanding the pathogenesis of ciliopathies or other renal conditions.