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Abstract: PO1991

A Novel Insulin Sensitizer Targeting Nuclear Receptor PPARγ Provides Beneficial Effects in a Glomerular Disease Model

Session Information

  • Podocyte Biology
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

  • 1204 Podocyte Biology

Authors

  • 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
  • Kerlin, Bryce A., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Neves, Francisco R., Universidade de Brasília, Brasilia, Brazil
  • Agrawal, Shipra, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
Background

Thiazolidinediones (TZDs) are nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) agonists traditionally used to treat type II diabetes due to their insulin-sensitizing effects. These have recently been demonstrated to be beneficial in protecting podocytes and reducing proteinuria in glomerular disease. Since these FDA-approved drugs are associated with adverse effects such as weight gain, edema, bone loss and increased risk for heart failure and bladder cancer, we hypothesized that disparate beneficial vs. adverse molecular activities of PPARγ can be modulated. We determined if GQ-16, a novel insulin sensitizer and a partial PPARγ agonist, which de-phosphorylates PPARγ at Ser273 like other TZDs, provides therapeutic advantage in glomerular disease.

Methods

The studies were approved by the Institutional Animal Care and Use Committee at Nationwide Children’s Hospital. Proteinuria was induced in male Wistar rats by single intravenous puromycin amino-nucleoside (PAN) injection, while the control group received saline. PAN-injected rats received sham vehicle, pioglitazone (Pio) or GQ-16 by oral gavage daily (n = 7/group). The rats were weighed daily, and urine samples were collected and analyzed for proteinuria. Plasma with sodium citrate and corn trypsin inhibitor was collected from the inferior vena cava. Endogenous thrombin potential was determined by thrombin generation assay.

Results

PAN induced robust proteinuria (P=0.009) on Day 11 and Pio reduced PAN-induced proteinuria significantly with 63.3% mean reduction (P=0.038). Interestingly, GQ-16 reduced proteinuria even further by 81.2% (P=0.008), and these were comparable to healthy control levels (ns, P=0.66). Furthermore, proteinuria reduction correlated with correction of disease associated hyper-coagulopathy. GQ-16 improved PAN-induced hyper-coagulopathy as measured by improved endogenous thrombin potential and peak thrombin. No significant differences in body weights were observed in treatment vs. PAN groups.

Conclusion

GQ-16, a novel insulin sensitizer and partial PPARγ agonist, shows better efficacy profile in an experimental glomerular disease model than Pio, a traditional TZD with full PPARγ agonistic activity.

Funding

  • Private Foundation Support