Glucocorticoid- and pioglitazone-induced proteinuria reduction in experimental NS both correlate with glomerular ECM modulation

Sagar Bhayana; Julie A Dougherty; Yu Kamigaki; Shipra Agrawal; Saranga Wijeratne; James Fitch; Amanda P Waller; Katelyn J Wolfgang; Peter White; Bryce A Kerlin; William E Smoyer

doi:10.1016/j.isci.2023.108631

Glucocorticoid- and pioglitazone-induced proteinuria reduction in experimental NS both correlate with glomerular ECM modulation

iScience. 2023 Dec 2;27(1):108631. doi: 10.1016/j.isci.2023.108631. eCollection 2024 Jan 19.

Authors

Sagar Bhayana¹, Julie A Dougherty¹, Yu Kamigaki¹, Shipra Agrawal^{1

2}, Saranga Wijeratne³, James Fitch³, Amanda P Waller¹, Katelyn J Wolfgang¹, Peter White^{2

3}, Bryce A Kerlin^{1

2}, William E Smoyer^{1

2}

Affiliations

¹ Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
² Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
³ Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.

Abstract

Idiopathic nephrotic syndrome (NS) is a common glomerular disease. Although glucocorticoids (GC) are the primary treatment, the PPARγ agonist pioglitazone (Pio) also reduces proteinuria in patients with NS and directly protects podocytes from injury. Because both drugs reduce proteinuria, we hypothesized these effects result from overlapping transcriptional patterns. Systems biology approaches compared glomerular transcriptomes from rats with PAN-induced NS treated with GC vs. Pio and identified 29 commonly regulated genes-of-interest, primarily involved in extracellular matrix (ECM) remodeling. Correlation with clinical idiopathic NS patient datasets confirmed glomerular ECM dysregulation as a potential mechanism of injury. Cellular deconvolution in silico revealed GC- and Pio-induced amelioration of altered genes primarily within podocytes and mesangial cells. While validation studies are indicated, these analyses identified molecular pathways involved in the early stages of NS (prior to scarring), suggesting that targeting glomerular ECM dysregulation may enable a future non-immunosuppressive approach for proteinuria reduction in idiopathic NS.

Keywords: Gene network; Nephrology; Systems biology; Transcriptomics.

Abstract

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