Abstract: SA-PO544

Chemical Genetic Screen Reveals Novel Role for PPAR Signaling in Renal Progenitor Development

Session Information

  • Developmental Biology
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Developmental Biology and Inherited Kidney Diseases

  • 401 Developmental Biology

Authors

  • Chambers, Joseph M., University of Notre Dame, Notre Dame, Indiana, United States
  • Wingert, Rebecca A., University of Notre Dame, Notre Dame, Indiana, United States
Background

The genetic and molecular mechanisms directing nephron segmentation during kidney development are not well understood. Deregulation of genes involved in kidney development result in a variety of diseases broadly categorized as Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). Embryonic zebrafish have a simplified kidney, the pronephros, comprised of proximal and distal segments that display conservation with mammalian nephrons, including humans, thus enabling CAKUT modeling.

Methods

Through a novel chemical genetic screen, we discovered that peroxisome proliferator-activated receptor (PPAR) signaling is essential for normal nephron segment development. PPARs are a group of nuclear receptor proteins that are activated by ligands such as fatty acids and act as transcription factors by heterodimerization with retinoid X receptor (RXR) to regulate cell differentiation and perform diverse roles in metabolism. We found that treatment with the PPAR agonist bezafibrate during nephrogenesis alters the balance of proximal and distal cells. Interestingly, pparg co-activator, ppargc1a, which binds to activated PPARs to regulate transcription of target genes, is dynamically expressed in renal progenitors.

Results

To test the functional role of this co-activator during nephron segmentation, we examined nephron development in ppargc1asa13186 mutants, where a lesion in exon 8 with a TàA substitution results in a premature STOP codon and an anticipated loss of the RNA processing domain. ppargc1asa13186 mutants have an abrogated distal tubule and increased proximal tubule domain, which was recapitulated in subsequent knockdown studies as well. Further, ppargc1a knockout and knockdown models development renal cysts, a hallmark of dysplastic CAKUT. Interestingly, there is a decrease in cilia within the nephrons of mutant and knockdown examples. Assessment of essential nephron regulators revealed that ppargc1a acts to inhibit irx3b and promote tbx2b.

Conclusion

Taken together, our studies suggest a novel mechanism by which PPAR signaling coordinates lineage choices during nephrogenesis. These findings may lead to a better understanding of the therapeutic value of PPARs in relation to renal birth defects and cystic disease conditions as well.

Funding

  • NIDDK Support