Abstract: TH-PO0346
Proteinuria Reduction by Methylprednisolone, Pioglitazone, and Mifepristone Is Mediated by Shared Gene Expression and Pathway Remodeling in Experimental Nephrotic Syndrome
Session Information
- Glomerular Diseases: Omics
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Perumal, Achintya, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Dougherty, Julie, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Bhayana, Sagar, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Kamigaki, Yu, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Brinton, Lindsey T., PharmaDirections, Research Triangle Park, North Carolina, United States
- Stojkic, Ivana, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
- Eddy, Sean, Michigan Kidney Translational Medicine Center, Ann Arbor, Michigan, United States
- Hartman, John R., Michigan Kidney Translational Medicine Center, Ann Arbor, Michigan, United States
- Smoyer, William E., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States
Background
Idiopathic nephrotic syndrome (NS) is the most common glomerular disease affecting children. The current standard therapy is glucocorticoids, which is effective but associated with significant toxicity, including immunosuppression. Our data show that pioglitazone (Pio; a type II diabetes drug) and mifepristone (MIF; an anti-progestin used in abortion care) also reduce proteinuria in NS models. Methylprednisolone (MP) is a glucocorticoid receptor agonist, while Pio is a PPARg receptor agonist, and MIF is a dual glucocorticoid and progesterone receptor antagonist. Since all 3 drugs target nuclear receptors, we hypothesized that their proteinuria-reducing effects in NS share common glomerular transcriptional pathways.
Methods
Male Wistar rats were given 50 mg/kg puromycin aminonucleoside (PAN) and treated once daily with vehicle, MP (15 mg/kg IP), Pio (10 mg/kg PO), or MIF (2.5 mg/kg IP). Glomerular RNAseq identified differential gene expression among treatments. Subsequent Ingenuity Pathway Analysis and Gene Set Variation Analysis found both commonly and uniquely altered pathways.
Results
All three drugs reduced PAN-induced proteinuria (MP=95%; Pio=93%; MIF=89%). Glomerular transcriptomic analyses revealed 183 commonly regulated genes, many of which were enriched in cell cycle–related processes. In addition, pathway analyses revealed overlap in signaling networks regulating actin cytoskeleton organization, known to be essential for podocyte structure and function. Among the most altered common pathways were Rho GTPases Activate Formins, VDR/RXR Activation, and WNT/B-catenin Signaling. While MP and Pio shared more overlapping genes, MP and MIF shared more overlapping pathways. We also identified MP-specific gene signatures associated with immunosuppressive pathways, providing insight into the known adverse effects of standard NS therapy.
Conclusion
Together, these results define shared glomerular transcriptional programs underlying proteinuria reduction and highlight potential therapeutic pathways that may enable non-immunosuppressive treatment strategies for NS. The similarity in gene amelioration and pathway alteration shared by MP and Pio suggests that podocyte nuclear receptor modulation via PPARγ agonism could be an effective steroid-sparing strategy for proteinuria reduction in NS and other glomerular diseases.
Acknowledgment
The present study was supported by a grant from the National Institutes of Health NIDDK R01 (DK 095059) to W.E.S.
Funding
- NIDDK Support