Clathrin-Mediated HMGB1 Endocytosis Promotes Acute Kidney Ischemia-Reperfusion-Induced Lung Injury
- AKI: Mechanisms - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- Kuai, Yuxian, Children’s Hospital of Soochow University, Suzhou, JiangSu, China
- Li, Yanhong, Children’s Hospital of Soochow University, Suzhou, JiangSu, China
Acute kidney injury (AKI) further increases mortality when combined with acute lung injury (ALI). Blockade of high mobility group box1 (HMGB1) may reduce AKI induced ALI. However, the potential molecular mechanisms in kidney-lung crosstalk after AKI remain elusive. We hypothesized that circulating HMGB1, released form ischemia-reperfusion (I/R) injured kidney, enters the lung cells and promotes AKI induced ALI by modulating neutrophil extracellular traps (NETs) formation.
Workflow of the study is shown in Fig.
Analysis of cytokines and chemokines and lung histology revealed increased lung inflammation and injury following kidney I/R. Serum HMGB1 level increased gradually with the continued extracellular release of HMGB1 from kidney cells following the extension of I/R time. The interaction of clathrin, screened by mass spectrometry, with HMGB1 and its receptor TLR4 in lung endothelial cells was confirmed by co-IP and IF co-localization, and the lung specific knockdown of clathrin decreased lung inflammation and injury induced by kidney I/R in mice. Increased expression of PAD4 and CitH3 and the co-localization of CitH3 and MPO suggested that kidney I/R induced NETs formation in lung. Blockade of HMGB1 by neutralizing antibody in vivo and knockdown of HMGB1 in vitro inhibited NETs formation and ameliorated AKI induced ALI.
HMGB1 released from I/R kidney promotes AKI-induced ALI in mice by modulating NETs, and clathrin-mediated endocytosis is required for HMGB1-TLR4 to enter lung endothelial cells and regulate neutrophils infiltration. Induced NETs formation leads to lung injury that could be rescued by HMGB1 neutralizing antibody, suggesting that targeting NETs and the HMGB1 pathway might extend effective therapeutic strategies to minimize AKI-induced ALI.