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Abstract: PO1725

Glucocorticoid- and Pioglitazone-Induced Proteinuria Reduction Correlates with Glomerular Extracellular Matrix Remodeling in Experimental Nephrotic Syndrome

Session Information

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
  • 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
  • White, Peter, 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 a common glomerular disease in children. While glucocorticoids (GC) are the mainstay of childhood NS treatment, pioglitazone (Pio; an FDA-approved PPARg agonist to treat type 2 diabetes) has been reported to reduce proteinuria in experimental NS and to directly protect podocytes from injury. Since both GC and Pio activate nuclear receptors (NR3C1 and PPARG, respectively) we hypothesized that their proteinuria-reducing effects result from overlapping glomerular gene transcriptional patterns.

Methods

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

Results

Unsupervised clustering revealed partial reversibility of PAN-associated mRNA dynamics by treatment with either GC or Pio. IPA analyses + web-based bioinformatic platforms identified 29 genes-of-interest common to GC- and Pio-induced proteinuria reduction, which included ECM remodeling, lipid metabolism, DNA-binding and cytoskeletal organization. Based on expression differences using real-time PCR, 29 genes-of-interest were selected for further analysis, which on clinical correlation with a human FSGS database (Nephroseq) suggested a direct relevance of glomerular ECM regulation in NS. Also, glomerular cell deconvolution using published single-cell glomerular transcriptome profiles identified podocyte- and mesangial cell-specific perturbations in gene expression during NS and with treatments. Finally, validation of selected genes-of-interest using PAN-induced injury of human podocytes and mesangial cells confirmed significant upregulation of LGALS3 (primary role in cell adhesion) and MMP2/ACTA2 (primary role in ECM degradation/cell motility or integrity) respectively.

Conclusion

These studies identified podocyte- and mesangial cell-specific transcripts common to both proteinuria-reducing treatments that identify possible targets for future treatment for NS