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Kidney Week

Abstract: TH-PO042

Pretreatment with Roxadustat (FG-4592) Attenuates Folic Acid-Induced Kidney Injury by Decreasing Ferroptosis

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Author

  • Li, Xue, Department of Histology and Embryology, Shen yang, China
Background

Folic acid (FA)-induced kidney injury model is characterized by progressive tubular damage at early stage and interstitial fibrosis at later stage. Ferroptosis, has been thought to be one of the main causes for the acute kidney injury (AKI) by the iron-dependent accumulation of lipid peroxidation, therefore disrupting antioxidant defense system. FG-4592 is hypoxia inducible factor (HIF) prolyl hydroxylase inhibitor (HIF-PHI) often used for improving anemia in patients with chronic kidney disease (CKD) through activating HIF-1a. What is more, precondition HIF-1a can enhance antioxidant capacity and iron mobilization through Nuclear erythroid 2 related factor 2 (Nrf2) signaling. Nrf2 is a key transcriptional factor which regulates almost all genes that are associated with ferroptosis. Given its anti-oxidant roles, FG-4592 was introduced in this study as a preconditionor to see if it had effects on FA-induced AKI and the mechanism.

Methods

Mice were divided into 4 groups,control group(n=12);FG-4592 group(n=12) pretreatment with FG-4592 for 2 days,mice were sacrificed 2 days (n=6 per group) or14 days later(n=6 per group) ;FA(folic acid-induced kidney injury ) group(n=12); FA + FG-4592 group(n=12).In FA and FA+FG-4592 groups,mice were sacrificed 2 days (n=6 per group) or14 days(n=6 per group) after folic acid injection.Renal function,renal morphology,MDA,4-HNE,GSH,Fe,HIF-1a,Nrf2,GPX4,HO-1,SLC7A11,ferroportion,IL-1β,TNF-α,F4/80,Fn,colIV,vimentin were assessed.

Results

pretreatment with FG-4592 improved kidney injury and inflammation in FA-induced kidney at early stage by upregulating antioxidant enzyme (GPX4 and HO-1) and GSH, meanwhile downregulating lipid peroxidation (MDA and 4-HNE) and iron. Furthermore, FG-4592 activated Nrf2 and upregulated antioxidant enzyme (GPX4 and HO-1), SLC7A11 (responsible for GSH synthesisthe) and ferroportin (an iron export protein), resulting in a reduction of ferroptosis. Further studies showed that Nrf2 was up-regulated by increased AKT and GSK-3βphosphorylation. Finally, pretreatment with FG-4592 ameliorated kidney fibrosis at later stage after FA-induced kidney injury.

Conclusion

pretreatment with FG-4592 plays an important role in the prevention of the transition from AKI to CKD through Nrf2-mediated anti-ferroptosis, and pretreatment with FG-4592 prevents FA-induced kidney injury partially via the AKT/GSK-3β-mediated Nrf2 activation.