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Abstract: PO1689

Selective PPARγ Modulator with Reduced Adipogenic Potential Ameliorates Experimental Nephrotic Syndrome

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • Burton, Claire, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Rask, Galen, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Waller, Amanda P., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Webb, Amy, The Ohio State University, Columbus, Ohio, United States
  • da Rocha Pitta, Marina Galdino, Universidade Federal de Pernambuco, Recife, PE, Brazil
  • Amato, Angélica Amorim, Universidade de Brasilia, Brasilia, DF, Brazil
  • Cianciolo, Rachel, The Ohio State University, Columbus, Ohio, United States
  • Becknell, Brian, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Kerlin, Bryce A., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Neves, Francisco R., Universidade de Brasilia, Brasilia, DF, Brazil
  • Fornoni, Alessia, University of Miami School of Medicine, Miami, Florida, United States
  • Agrawal, Shipra, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
Background

Glomerular disease, often manifesting as nephrotic syndrome (NS) with high proteinuria, can be refractory to standard treatment and is typically associated with hypoalbuminemia, hypercholesterolemia, and hypercoagulopathy. We hypothesized that the nuclear receptor PPARγ can be selectively modulated using a novel partial agonist, GQ-16, to gain therapeutic advantage over traditional PPARγ agonists for NS treatment

Methods

Pio and GQ-16 were administered daily to male Wistar rats with puromycin amino-nucleoside (PAN)-induced nephropathy. Serum and urine chemistries were performed and kidneys, glomeruli, liver, and white adipose tissue (WAT) were harvested for RNA and protein extraction. Blood was collected for determination of thrombin generation parameters.

Results

PAN induced robust proteinuria, which was significantly reduced with Pio to 64% of PAN-value, and robustly with GQ-16 to 81% of PAN, which was comparable to controls. Podocyte hypertrophy also returned to normal with Pio and GQ-16. While both GQ-16 and Pio restored glomerular Nphs1 and hepatic Pcsk9 expression and reduced hypercholesterolemia, GQ-16 also restored glomerular Nrf2, and reduced disease-associated hypoalbuminemia and hypercoagulopathy. Furthermore, RNA-seq analysis identified both common and distinct glomerular genes altered by Pio and GQ-16 treatments. Moreover, Pio but not GQ-16 significantly induced aP2 (fatty acid binding protein) in adipocytes and in WAT. Both, Pio and GQ-16 induced insulin sensitizing adipokines in WAT with varying degrees

Conclusion

Selective modulation of PPARγ by a partial agonist may be a more beneficial approach than a full PPARg agonist in reducing proteinuria, hypoalbuminemia, and hypercoagulopathy in NS and in decreasing drug-associated side effects such as adipogenesis and weight gain.

Funding

  • Other NIH Support