摘要：SummaryGlomerular disease manifests as nephrotic syndrome (NS) with high proteinuria and comorbidities, and is frequently refractory to standard treatments. We hypothesized that a selective modulator of PPARγ, GQ-16, will provide therapeutic advantage over traditional PPARγ agonists for NS treatment. We demonstrate in a pre-clinical NS model that proteinuria is reduced with pioglitazone to 64%, and robustly with GQ-16 to 81% of nephrosis, comparable to controls. Although both GQ-16 and pioglitazone restore glomerular-Nphs1, hepatic-Pcsk9and serum-cholesterol, only GQ-16 restores glomerular-Nrf2, and reduces hypoalbuminemia and hypercoagulopathy. GQ-16 and pioglitazone restore common and distinct glomerular gene expression analyzed by RNA-seq and induce insulin sensitizing adipokines to various degrees. Pioglitazone but not GQ-16 induces more lipid accumulation andaP2in adipocytes and white adipose tissue. We conclude that selective modulation of PPARγ by a partial agonist, GQ-16, is more advantageous than pioglitazone in reducing proteinuria, NS associated comorbidities, and adipogenic side effects of full PPARγ agonists.Graphical abstractDisplay OmittedHighlights•Selective Modulation of PPARγ offers therapeutic advantage over full agonism in NS•GQ-16 reduces proteinuria in NS and associated comorbidities with high efficacy•RNA-Seq identified common and distinct glomerular gene expression by GQ-16 and pioglitazone•Pioglitazone induces more markers of adipogenesis, and GQ-16 induces adipokines to a greater degreeNephrology; Molecular physiology; Cell biology
