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ASN / Education & Meetings / Kidney Week /
Abstract: SA-PO710

Similarities and Differences in Gene Expression between Glucocorticoids and Pioglitazone in a Rodent Model of Nephrotic Syndrome

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

  • Kamigaki, Yu, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Dougherty, Julie, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Bhayana, Sagar, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Waller, Amanda P., The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Kerlin, Bryce A., The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
  • Smoyer, William E., The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
Background

Idiopathic nephrotic syndrome (INS) is one of the most frequent glomerular diseases in children with first line treatment of glucocorticoids (GCs), an immunosuppressant with myriad side effects. Thus, there is a critical need to develop more effective and less toxic options. Pioglitazone (Pio), a non-immunosuppressant, is FDA-approved for type 2 diabetes mellitus. Pio has been associated with proteinuria reduction in adults and children with NS, so it has potential as a non-immunosuppressive alternative or supplement to GC treatment. Therefore, we wanted to compare changes in gene expression and pathways between the two drugs.

Methods

Male Wistar rats received 50 mg/kg puromycin aminonucleoside (PAN) or saline injection and treated daily with vehicle, methylprednisolone (MP, 15 mg/kg), or Pio (10 mg/kg). Rats were euthanized on day 11 and glomerular RNA was sequenced. Differentially expressed genes were analyzed for pathway activation, upstream regulators, and causal networks.

Results

MP and Pio significantly improved proteinuria compared to PAN-only treated animals. We filtered glomerular data for genes significantly up- or down-regulated in PAN-treated animals compared to controls, then compared expression of PAN + MP and PAN + Pio. Our recent article addressed PAN-induced up-regulated genes ameliorated by both drugs. This study analyzed the PAN-induced down-regulated genes commonly improved by both drugs. Common upstream regulators included calcitriol, EGLN family, KRAS, MYOD1, and SORL1. We also analyzed expression changes unique to either drug. MP had 46 unique upstream regulators, including immune regulators and transcription regulators such as HDAC1/2, TBX3, and ATF3. The list of uniquely altered genes for Pio was too short for pathway analysis but included CD36, IL34, RHOQ, and SHPRH, among others.

Conclusion

These studies illustrated the common and unique changes in glomerular gene expression in a rodent NS model treated with immunosuppressive (MP) and non-immunosuppressive (Pio) drug.

Funding

  • NIDDK Support