Release of extracellular DNA influences renal ischemia reperfusion injury by platelet activation and formation of neutrophil extracellular traps

Acute kidney injury is often the result of ischemia reperfusion injury, which leads to activation of coagulation and inflammation, resulting in necrosis of renal tubular epithelial cells. Platelets play a central role in coagulation and inflammatory processes, and it has been shown that platelet act...

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Bibliographic Details
Published in:Kidney international Vol. 91; no. 2; p. 352
Main Authors: Jansen, Marcel P B, Emal, Diba, Teske, Gwendoline J D, Dessing, Mark C, Florquin, Sandrine, Roelofs, Joris J T H
Format: Journal Article
Language:English
Published: United States 01.02.2017
Subjects:
Animals
Blood Platelets - drug effects
Blood Platelets - metabolism
Cell Line
Disease Models, Animal
DNA - genetics
DNA - metabolism
Epithelial Cells - drug effects
Epithelial Cells - metabolism
Epithelial Cells - pathology
Extracellular Traps - metabolism
Humans
Kidney Tubular Necrosis, Acute - genetics
Kidney Tubular Necrosis, Acute - metabolism
Kidney Tubular Necrosis, Acute - pathology
Kidney Tubular Necrosis, Acute - prevention & control
Kidney Tubules - drug effects
Kidney Tubules - metabolism
Kidney Tubules - pathology
Male
Mice, Inbred C57BL
Nephritis - genetics
Nephritis - metabolism
Nephritis - pathology
Platelet Activation - drug effects
Platelet Aggregation Inhibitors - pharmacology
Platelet Factor 4 - metabolism
Reperfusion Injury - genetics
Reperfusion Injury - metabolism
Reperfusion Injury - pathology
Reperfusion Injury - prevention & control
Signal Transduction
Ticlopidine - analogs & derivatives
Ticlopidine - pharmacology
Time Factors
ischemia reperfusion
acute kidney injury
inflammation
renal pathology
platelets
ISSN:1523-1755, 1523-1755
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Summary:Acute kidney injury is often the result of ischemia reperfusion injury, which leads to activation of coagulation and inflammation, resulting in necrosis of renal tubular epithelial cells. Platelets play a central role in coagulation and inflammatory processes, and it has been shown that platelet activation exacerbates acute kidney injury. However, the mechanism of platelet activation during ischemia reperfusion injury and how platelet activation leads to tissue injury are largely unknown. Here we found that renal ischemia reperfusion injury in mice leads to increased platelet activation in immediate proximity of necrotic cell casts. Furthermore, platelet inhibition by clopidogrel decreased cell necrosis and inflammation, indicating a link between platelet activation and renal tissue damage. Necrotic tubular epithelial cells were found to release extracellular DNA, which, in turn, activated platelets, leading to platelet-granulocyte interaction and formation of neutrophil extracellular traps ex vivo. Renal ischemia reperfusion injury resulted in increased DNA-platelet and DNA-platelet-granulocyte colocalization in tissue and elevated levels of circulating extracellular DNA and platelet factor 4 in mice. After renal ischemia reperfusion injury, neutrophil extracellular traps were formed within renal tissue, which decreased when mice were treated with the platelet inhibitor clopidogrel. Thus, during renal ischemia reperfusion injury, necrotic cell-derived DNA leads to platelet activation, platelet-granulocyte interaction, and subsequent neutrophil extracellular trap formation, leading to renal inflammation and further increase in tissue injury.
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ISSN:1523-1755
1523-1755
DOI:10.1016/j.kint.2016.08.006