Glucocorticoid- and Pioglitazone-Induced Proteinuria Reduction in Experimental Nephrotic Syndrome Both Correlate with Glomerular ECM Modulation
Idiopathic nephrotic Syndrome (NS) is a common glomerular disease. While glucocorticoids (GC) are the primary treatment, the PPAR? agonist pioglitazone (Pio) also reduces proteinuria in patients with NS and directly protects podocytes from injury. Since 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. Overall design: Day 11 glomeruli were isolated from rats with PAN-induced NS treated with methylprednisolone or with pioglitazone. Sham treated health controls were included as reference. N=4 rats were used for RNAseq. Data were analyzed for PAN-induced changes in gene expression and amelioration of said alterations by either drug. This study focused on the overlapping amerliorations of disease-induced gene expression between methylprednisolone and pioglitazone.