Abstract: FR-PO161
Erythropoietin and Its Derived Peptide Helix B Surface Peptide in Ischemia-Reperfusion Induced AKI, Repair, or Fibrosis
Session Information
- AKI: Mechanisms - II
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Han, Cheng, Affiliated Hospital of Nantong University, Nantong, China
- Wu, Yuanyuan, Nantong University, Nantong, China
- Chen, Fei, Affiliated Hospital of Nantong University, Nantong, China
- Sai, Wenli, Affiliated Hospital of Nantong University, Nantong, China
- Yang, Bin, University of Leicester, Leicester, United Kingdom
Background
Ischemia-reperfusion (IR)-induced acute kidney injury (AKI) often progresses to chronic kidney disease. Erythropoietin (EPO) and its derivative, helix B surface peptide (HBSP), significantly ameliorates AKI, but may lead to different outcomes at the late stage and their underlying mechanisms remain unclear. The effects and mechanisms of single and/or multiple administrations of high-dose EPO and HBSP are studies in IR induced-AKI, repair or fibrosis.
Methods
Mouse kidney epithelial TCMK-1 cells were stimulated by hydrogen peroxide (H2O2) for 24 h or recombinant transforming growth factor β (TGF-β) for 72 h, to mimic IR-related acute and chronic kidney injury respectively, with or without the treatment of 25-800 IU/mL EPO or 10-80 ng/mL HBSP. In addition，a mouse renal IR model was established by obstructed bilateral renal pedicles for 30 min and reperfused for 2 weeks. Mice were treated with 5000 IU/kg EPO at the onset of surgery and/or every 3 days onwards, or 24 nmol/kg HBSP only once. The protein level of HMGB1 and α-SMA, renal function and histology were assessed.
Results
H2O2 stimulation significantly increased HMGB1 expression in TCMK-1 cells at 24 h, which was decreased by 100 IU/mL EPO, but not 200-800 IU/mL EPO; and dose-dependently decreased by 20-80 ng/mL HBSP. TGF-β treatment greatly raised the level of α-SMA in TCMK-1 cells at 72 h, which was decreased by 50 IU/mL EPO, but not 100-800 IU/mL EPO, and gradually reduced by 20-80 ng/mL HBSP. In the in vivo model, HBSP and a single dose of EPO both markedly improved kidney function and structure, reduced HMGB1 and α-SMA protein, but increased E-cadherin protein. However, the multiple high-dose EPO did not show such impact. In addition, HBSP, but not EPO, greatly increased p-STAT5 protein in IR kidneys. Furthermore, the single dose of HBSP and multiple doses of EPO downregulated EPOR/βcR expression in IR kidneys, which was not altered by the single usage of EPO.
Conclusion
The low dosage of EPO and HBSP reduced inflammatory and fibrotic mediators in TCMK-1 cells, while single usage of EPO and HBSP attenuated renal injury with HBSP further reduced fibrosis. The different long-term roles of both in IR kidneys may attribute to the status of STAT5 pathway, but exact underlying mechanisms including EPOR/βcR involvement still need to be further explored.