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Abstract: TH-OR014

High Mobility Group Box 1(HMGB1)-Induced Ferroptosis Accelerates Ischemia-Reperfusion-Incited AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Xu, Gang, Huazhong University of Science and Technology, Tongji Medical College, Tongji Hospital, Wuhan, China
  • Zhao, Zhi, Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • Yao, Ying, Huazhong University of Science and Technology, Tongji Medical College, Tongji Hospital, Wuhan, China
  • Zeng, Rui, Tongji Hospital, Huazhong Univ of Science and Technology, Wuhan, HUBEI, China
Background

Regulated necrosis (RN), which is identified as cells death in a regulated manner but with the morphologic features of necrosis, has been implicated to be involved in the process of AKI and improve chronic kidney injury. The common hallmark of RN in kidneys is the rupture of tubular epithelial cell membrane and the release of the unprocessed intracellular components known as damage-associated molecular patterns (DAMPs) resulting in activation of immune system. As a representative DAMP molecular, high mobility group box-1 (HMGB1) involving in many inflammatory diseases has less determined on the effect of RN.

Methods

Mice with conditional alleles of HMGB1 were crossed with mice harboring Ksp-CreERT transgenes to knock out HMGB1 in renal tubular epithelial cells. 8-10 weeks old HMGB1fl/fl; Ksp-CreERT+/+ mice were randomly divided into two groups: KH+TMX group and KH+Vehi group. The two groups were injected with tamoxifen(TMX) at a dose of 100 mg/kg body weight and Vehicle for 5 consecutive days respectively. After two weeks of elution, the mice were subjected to 30 min of bilateral ischemia reperfusion (I/R). One day later, the mice were sacrificed and the serum, kidney, liver, and other organs were sampled for evaluating the role of HMGB1 in I/R.

Results

Renal tubular specific HMGB1 knockout mice underwent a pronounced pathological shift including decreased expression of KIM-1 and NGAL and upregulated expression of Klotho after I/R. Serum creatinine and urea nitrogen were reduced in KH+TMX group with less renal inflammatory cell infiltration. Ferroptosis and necroptosis are the most described in RN. We found that HMGB1 knockout ameliorated ferroptosis in I/R. KH+TMX group got a higher expression of GPX4 and lower level of ACSL4 in kidney with less accumulation of lipid peroxidation. However, the key enzymes of necroptosis, RIP1/RIP3/MLKL, have less changed in KH-TMX group compared to the control group. RNA-seq further indicated 710 genes differentially expressed between KH-TMX and KH-Vehi group. The results of GO analysis and the KEGG pathway analysis illustrated that a large amount of differentially expressed genes (DEGs) were involved in lipid metabolic and amino acid process which is tightly linked to the regulation of ferroptosis.

Conclusion

HMGB1-dependent ferroptosis impairs the ischemia-induced AKI, which might serve as a novel target for I/R treatment.

Funding

  • Government Support - Non-U.S.