Abstract: SA-PO0761
Comparison of Gene Expression Alterations Induced by Glucocorticoids, Thiazolidinediones, and Mifepristone Associated with Proteinuria Reduction in Puromycin Aminonucleoside-Induced Nephrotic Syndrome (PAN-NS)
Session Information
- Glomerular Diseases: Profiling Through Multiomics
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Perumal, Achintya, Nationwide Children's Hospital, Columbus, Ohio, United States
- Dougherty, Julie, Nationwide Children's Hospital, Columbus, Ohio, United States
- Bhayana, Sagar, Nationwide Children's Hospital, Columbus, Ohio, United States
- Brinton, Lindsey T, Cypress Biopharma, Cary, North Carolina, United States
- Stojkic, Ivana, Nationwide Children's Hospital, Columbus, Ohio, United States
- Zhang, Gaofu, Nationwide Children's Hospital, Columbus, Ohio, United States
- Eddy, Sean, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Hartman, John R., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Smoyer, William E., Nationwide Children's Hospital, Columbus, Ohio, United States
Background
Idiopathic Nephrotic syndrome (INS) is a prevalent glomerular disease affecting children. Currently, the most widely used treatments are glucocorticoids (GCs) which have numerous side effects. Pioglitazone (Pio) is a non-immunosuppressant thiazolidinedione (TZD), FDA-approved treatment for type 2 diabetes mellitus. Moreover, it has also been associated with reduced proteinuria in adults and children with INS. Mifepristone is a synthetic steroid and GC receptor antagonist that is FDA-approved for pregnancy termination (in combination with misoprostol) and for treating hyperglycemia in Cushing syndrome. It is used off-label to treat steroid-dependent NS or frequently relapsing NS in children. We hypothesized there would be common and disparate alterations in glomerular gene expression among the 3 drugs for reducing proteinuria in PAN-NS rats. Here we are focused on distinct alterations in gene expression induced by each drug.
Methods
Male Wistar rats received 50 mg/kg puromycin aminonucleoside (PAN) and were treated daily with vehicle, the GC methylprednisolone (MP, 15 mg/kg), Pio (10 mg/kg), or Mifepristone (RU486, 2.5mg/kg). Glomerular RNA was isolated for sequencing. We filtered data for significant changes in gene expression for PAN + drug vs. PAN-treated animals. Gene expression was analyzed with Qiagen’s Ingenuity Pathway Analysis (IPA) software.
Results
All 3 drugs reduced median proteinuria in PAN-NS animals compared to diseased animals. Among the most dysregulated pathways associated with GCs were 1) glycogen metabolism, 2), cAMP-mediated signaling, and 3) RhoA signaling. Among the most affected pathways for TZDs were 1) lipid metabolism by PPARα (inhibition), 2) LXR/RXR activation (inhibition), and 3) neutrophil degranulation (inhibition). Pathways most dysregulated by RU486 included 1) tRNA processing in the mitochondrion, 2) CLEAR Signaling Pathway, and 3) rRNA processing.
Conclusion
These studies have identified several distinct drug-induced pathways associated with proteinuria reduction in PAN-NS. Future targeting of one or more of these pathways could enable the development of novel approaches to reduce proteinuria in INS and other glomerular diseases.
Funding
- NIDDK Support