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Abstract: PO2005

Glomerular Transcriptomic Analysis of Glucocorticoid- and Pioglitazone-Treated Nephrotic Syndrome

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

  • Bhayana, Sagar, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Agrawal, Shipra, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Chanley, Melinda A., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Waller, Amanda P., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Wolfgang, Katelyn, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Wijeratne, Saranga, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Fitch, James, Nationwide Children's Hospital, Columbus, Ohio, United States
  • Kerlin, Bryce A., Nationwide Children's Hospital, Columbus, Ohio, United States
  • Smoyer, William E., Nationwide Children's Hospital, Columbus, Ohio, United States
Background

Nephrotic Syndrome (NS) is among the most common glomerular diseases in children. Glucocorticoids (GC) are the primary treatment for NS, but 15-20% of children have or develop steroid resistant NS, creating an unmet need for novel treatments. Thiazolidinediones (TZDs) such as pioglitazone (Pio) have been reported to slow diabetic nephropathy progression, and to reduce proteinuria in animal models of NS. Since both GC and Pio act via binding to nuclear receptors we hypothesized that the reported similar degrees of proteinuria reduction by GC and Pio are driven via common molecular pathways.

Methods

We performed transcriptome analyses on glomeruli isolated from GC- and Pio-treated rats 11 days after induction of NS with PAN (n=4/group).

Results

Principal component analyses revealed distinct transcriptional profiles between control vs. PAN-treated rats, with 319 and 126 differentially up- and down-regulated genes in PAN respectively, which were largely reversed by both GC and Pio. Ingenuity pathway analyses (IPA) combined with drug-target interaction network analyses and gene set enrichment analyses identified 29 glomerular genes that were commonly regulated by GC, Pio, and their respective nuclear receptors (NR3C1 and PPARγ). Gene ontology annotation revealed these 29 genes to be involved in: ECM modification, plasma membrane dynamics, DNA damage/repair, transcription factor binding, lipid metabolism, and cytoskeletal organization. Gene segregation into their cells of origin using reported glomerular single cell transcriptomes revealed most dysregulation and restoration of gene expression within podocytes, with moderate changes within mesangial cells and minimal changes within endothelial cells. IPA-based disease and toxicity algorithms developed from these cell-specific data also revealed enhanced cytoskeletal organization and improved cell viability after both GC and Pio vs. PAN.

Conclusion

GC and Pio treatment reduced proteinuria similarly in NS, but by inducing alterations in both distinct and overlapping glomerular gene-sets. Notably, informatics analyses of overlapping genes identified ECM proteins, as potential novel targets for future therapies for NS, distinct from current immunosuppressive approaches.

Funding

  • NIDDK Support