#4425 EZH2 PROMOTES RENAL INTERSTITIAL FIBROSIS THROUGH DOWNREGULATION OF PHOSPHOENOLPYRUVATE CARBOXYKINASE 1 MEDIATED GLUCONEOGENESIS

Abstract Background and Aims Renal fibrosis is the common pathological pathway of various chronic kidney diseases progressing to end stage renal failure. The methyltransferase enhancer zeste homolog 2 (EZH2) has been identified as a therapeutic target inhibit interstitial fibrosis. However, mechanism underlying role EZH2 in not completely understood. Method Unilateral ureteral obstruction (UUO), unilateral ischemia-reperfusion injury (UIRI) mouse models were established. PCR, cleavage under targets tagmentation (CUT&Tag) Western blotting was performed evaluate expression phosphoenolpyruvate carboxykinase 1 (PCK1). Results By using inhibitor 3-DZNeP Ezh2 conditional knockout mice, we confirmed pro-fibrotic effect (UUO). Through RNA sequence analysis, found that (PCK1), critical enzyme gluconeogenesis, negatively regulated by fibrotic kidneys, which further quantitative CUT&Tag blotting. We showed deletion or inhibition inhibited enhanced PCK1 activity folic acid induced nephropathy. Moreover, dysregulated production glucose lactate UUO kidneys restored after 3-DZNeP. Finally, 3-mercaptopropionic (3-MPA) abrogated anti-fibrotic kidneys. Conclusion conclude promotes through mediated gluconeogenesis.