Abstract: TH-PO087
Kidney Injury Released HMGB1 Is a Pathogenic Agent to the Development of Acute Lung Injury
Session Information
- 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
Authors
- Hong, Yu, Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Yao, Ying, Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Zeng, Rui, Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Background
Acute kidney injury (AKI) could induce respiratory complications, resulting in a high mortality rate, but molecular mechanisms and mediators of AKI to acute lung injury (ALI) are not yet well understood.
Methods
Male C57BL/6 mice were used to establish bilateral renal ischemia-reperfusion injury (I/R) model. Single-cell RNA sequencing analysis was used to explore which molecule play a crucial role in AKI-ALI. The role of high mobility group box 1 (HMGB1) was verified by constructing renal tubular epithelial cell-specific HMGB1 knockout mice and injecting HMGB1 neutralizing antibodies. The post-translational modification of HMGB1 and its influence on other proteins in injured kidney was detected by the proteomic analysis. Immunoprecipitation, and immunofluorescence co-staining were used to identify the HMGB1 receptor in ALI.
Results
We found renal I/R induced ALI, especially at day one after surgery. The expression of HMGB1 in renal tubular cells increased rapidly after I/R, with the cytoplasmic migration of HMGB1. Specific knockout of HMGB1 in renal tubular cells or injection of HMGB1 neutralizing antibody alleviated AKI-induced ALI. The acetylation of HMGB1 in the kidney increased after I/R, which accelerates the release of HMGB1 into the peripheral circulation. In addition, we found 2469 sites of 1050 proteins were increased in acetylation compared to that in sham mice. Knockout of HMGB1 in renal tubular epithelial cells decreased acetylation of 1093 sites of 698 proteins, which are key proteins involved in several energy metabolism pathways. We further found that the binding receptor for HMGB1 on the membrane of lung tissue cells is depend on the advanced glycation end products (RAGE). After antagonizing RAGE, kidney I/R-induced ALI was alleviated, but kidney damage was not affected. It was further found that the HMGB1-RAGE axis participated in the progression of ALI via impairment of oxidative phosphorylation and the subsequent mitochondrial dysfunction.
Conclusion
Our work identifies HMGB1 released by the injured kidney as a causal key mediator of ALI, which provides a potential therapeutic target for this specific interorgan crosstalk of AKI to ALI.
Funding
- Government Support – Non-U.S.