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Kidney Week

Abstract: TH-PO041

Asparaginyl Endopeptidase Deficiency Protects Against AKI via Inhibition of Tubular Ferroptosis

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Chen, Chuanai, The School of Medicine, Nankai University, Tianjin, China
  • Tan, Xiaoyue, The School of Medicine, Nankai University, Tianjin, China
  • Wang, Dekun, The School of Medicine, Nankai University, Tianjin, China
  • Zhao, Yong, The School of Medicine, Nankai University, Tianjin, China
  • Yu, Yangyang, The School of Medicine, Nankai University, Tianjin, China

Lysosomal endopeptidase AEP (Asparaginyl Endopeptidase) is required for the maintenance of normal kidney physiology and homeostasis; AEP knockout aggravates interstitial fibrosis in the mouse model of obstructive nephropathy. However, role and underlying mechanism of AEP in the acute kidney injury (AKI) is unclear.


AKI was induced by bilateral ischemia–reperfusion of renal arteries or folic acid treatment in AEP+/+ and AEP-/- mice. We assessed the indexes of renal tubular injury, inflammatory infiltration and programmed cell death. Tubular injury markers Kim-1 and NAGL was measured as well. In vivo, ferroptosis was evaluated via assessment of MDA, 4-HNE and degradation of GPX4. In vitro, we compared hypoxia- or erastin- induced ferroptosis in the primary tubular cells isolated from AEP+/+ and AEP-/- mice. Supplement of FAC and downregulation of GPX4 were used to evaluate the role of AEP in hypoxia- or erastin- induced ferroptosis. Further, we analyzed the lysosomal degradation of GPX4. Coimmunoprecipitation was used to determine the interaction between AEP and GPX4. For tentative treatment, a synthetic AEP inhibitor RR-11a delivered by AEP-targeted nanoparticles was used in the IRI model.


AEP deficiency attenuated IRI-induced tubular injury, inflammation and programmed cell death compared with control. Ferroptosis, a regulated necrosis characterized with lethal lipid peroxidation was also inhibited in AEP-/- mice, manifested as decreased 4-HNE, MDA and degradation of GPX4. In vitro, ferroptosis induced either by hypoxia or by erastin was dampened in the primary AEP-/- tubular cells compared with AEP+/+control. Supplement of FAC or downregulation of GPX4 rescued ferroptosis in AEP-/- cells. IP assay and immunofluorescence staining showed interaction between AEP and GPX4. Moreover, knockout of AEP prevented lysosomal degradation of GPX4. Administration of RR-11a-containing nanoparticles ameliorated renal injury induced by IRI.


Our data suggest that interaction of AEP and GPX4 contributes to the lysosomal degradation of GPX4, facilitating the process of ferroptosis. Therefore, Deficiency of AEP inhibits ferroptosis and attenuates IRI-induced AKI. Inhibition of AEP could be a potential strategy benefit for the treatment of AKI.