Pulmonary endothelial cells endocytosis of HMGB1 promotes lung injury after renal ischemia-reperfusion injury
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PROVIDER: PRJNA1268538 | ENA |
REPOSITORIES: ENA
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Project description:Dysfunction of other organs is a significant contributor to the poor outcomes associated with acute kidney injury (AKI). HMGB1 is proposed to play a crucial role in the development of common extra-renal complications: acute lung injury (ALI). However, the mechanisms underlying these connections are not fully understood. Here, we established mice models of renal ischemia-reperfusion injury (IRI). HMGB1 was observed to be released from renal cell nucleus 1 hour after reperfusion. Based on mass spectrometry screening, clathrin was identified and the released HMGB1 entered pulmonary endothelial cells via clathrin-mediated endocytosis after binding to TLR4. Further investigations revealed that blocking HMGB1 with neutralizing antibodies or knocking down clathrin in lungs reversed pulmonary injury induced by renal IRI through inhibiting neutrophil recruitment and the formation and release of neutrophil extracellular traps (NETs) in lungs. Moreover, knocking down HMGB1 in TCMK-1 cells or clathrin in MPVECs in the co-culture systems in vitro obtained similar results. These findings demonstrate the effect of HMGB1 released from kidney in promoting ALI following renal IRI, disclose pulmonary endothelial cell endocytosis of HMGB1 mediated by clathrin as the potential mechanism, and identify neutralizing antibody to HMGB1 as a promising ALI mitigation strategy by inhibiting NETs formation in lungs.
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Project description:Ischemia/reperfusion injury (IRI) occurs in liver transplantations and major resections and can lead to liver dysfunction. HMGB1 locates in nucleus of normal hepatocytes, but translocates to cytoplasm and the extracellular space during IRI. Although the functions of nuclear and extracellular HMGB1 are well explored, the role cytoplasmic HMGB1 plays in hepatic IRI is still unknown. We hypothesize cytoplasmic HMGB1 interacts with binding proteins involved in the hepatocellular response to IRI. In this study binding proteins of cytoplasmic HMGB1 during hepatic IRI were identified. Normal and warm ischemia reperfusion (WI/R) liver tissues were used for cytoplasmic protein extraction. The protein extracts were subjected to co-immunoprecipitation to enrich HMGB1-protein complexes. To identify the immunoprecipitated proteins in eluates, 2DE and subsequent MS detection were performed. Three identified proteins were verified using western blotting: betaine--homocysteine S-methyltransferase 1 (BHMT), cystathionine gamma-lyase (CTH) and ATP synthase beta subunit (ATP5B). All three identified proteins have a role in metabolic pathways and autophagy. Our results demonstrate cytoplasmic HMGB1 binds to BHMT, CTH and ATP5B during hepatic WI/R. Since both, cytoplasmic HMGB1 and binding proteins, are involved in autophagy, we speculate this protein complex may be involved in the hepatocellular response to IRI via the autophagy pathway.
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Project description:Ischemic preconditioning is effective in limiting subsequent ischemic acute kidney injury in experimental models. microRNAs are an important class of post-transcriptional regulator and show promise as biomarkers of kidney injury. An evaluation was performed of the time- and dose-dependent effects of ischemic preconditioning in a rat model of functional (bilateral) ischemia-reperfusion injury. A short, repetitive sequence of ischemic preconditioning resulted in optimal protection from subsequent ischemia-reperfusion injury. A detailed characterization of microRNA expression in ischemic preconditioning/ischemia-reperfusion injury was performed by Exiqon miRCURY microRNA array.
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Project description:Ischemia-reperfusion injury (IRI) is a well-known model for acute kidney injury (AKI).
We applied proteomic analysis to detect membrane proteins from IRI mouse kidneys. The analysis set are composed of negative control (sham operation), samples of 4-hour after IRI, and samples of 8-hour IRI.
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Project description:Hepatic ischemia reperfusion injury is a dynamic process consisting of two stages: ischemia and reperfusion, and triggers a cascade of physiological and biochemical events. Given the important role of microRNAs in regulating gene expression, we analyzed gene expression changes in mouse livers at sham control, ischemia stage, and reperfusion stage. We generated global expression profiles of microRNA and mRNA genes in mouse livers subjected to ischemia reperfusion injury at the three stages, respectively. Comparison analysis showed that reperfusion injury had a distinct expression profile whereas the ischemia sample and the sham control were clustered together. Consistently, there are 69 differentially expressed microRNAs between the reperfusion sample and the sham control whereas 28 differentially expressed microRNAs between the ischemia sample and the sham control. We further identified two modes of microRNA expression changes in ischemia reperfusion injury. Functional analysis of both the differentially expressed microRNAs in the two modes and their target mRNAs revealed that ischemia injury impaired mitochondria function, nutrient consumption, and metabolism process. In contrast, reperfusion injury led to severe tissue inflammation that is predominantly an innate-immune response in the ischemia reperfusion process. Our staged analysis of gene expression profiles provides new insights into regulatory mechanisms of microRNAs in mouse hepatic ischemia reperfusion injury.
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