Extracellular histone release by renal cells after warm and cold ischemic kidney injury: Studies in an ex-vivo porcine kidney perfusion model.

Autor: van Smaalen TC; Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands., Beurskens DMH; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands., Kox JJHFM; Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands., Polonia R; Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands., Vos R; Department of Methodology and Statistics, School for Public Health and Primary Care (CAPHRI), Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands., Duimel H; Microscopy CORE Lab, Maastricht Multimodal Molecular Imaging Institute, FHML, Maastricht University, Maastricht, The Netherlands., van de Wetering WJ; Microscopy CORE Lab, Maastricht Multimodal Molecular Imaging Institute, FHML, Maastricht University, Maastricht, The Netherlands., López-Iglesias C; Microscopy CORE Lab, Maastricht Multimodal Molecular Imaging Institute, FHML, Maastricht University, Maastricht, The Netherlands., Reutelingsperger CP; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands., Ernest van Heurn LW; Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands., Peutz-Kootstra CJ; Department of Pathology, Maastricht University Medical Center, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands., Nicolaes GAF; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2023 Jan 20; Vol. 18 (1), pp. e0279944. Date of Electronic Publication: 2023 Jan 20 (Print Publication: 2023).
DOI: 10.1371/journal.pone.0279944
Abstrakt: Extracellular histones are cytotoxic molecules involved in experimental acute kidney injury. In patients receiving a renal transplant from donors after circulatory death, who suffer from additional warm ischemia, worse graft outcome is associated with higher machine perfusate extracellular histone H3 concentrations. We now investigated temperature-dependent extracellular histone release in an ex vivo porcine renal perfusion model, and subsequently studied histone release in the absence and presence of non-anticoagulant heparin. Seven pairs of ischemically damaged porcine kidneys were machine perfused at 4°C (cold ischemia) or 28°C (warm ischemia). Perfusate histone H3 concentration was higher after warm as compared to cold ischemia (median (IQR) = 0.48 (0.20-0.83) μg/mL vs. 0.02 (0.00-0.06) μg/mL; p = .045, respectively). Employing immune-electron microscopy (EM), histone containing cytoplasmic protrusions of tubular and endothelial cells were found after warm ischemic injury. Furthermore, abundant histone localization was detected in debris surrounding severely damaged glomerular cells, in a "buck shot" pattern. In vitro, histones were cytotoxic to endothelial and kidney epithelial cells in a temperature-dependent manner. In a separate ex vivo experiment, addition of heparin did not change the total histone H3 levels observed in the perfusate but revealed a continuous increase in the level of a lower molecular weight histone H3 variant. Our findings show that ischemically damaged kidneys release more extracellular histones in warm ischemia, which by EM was due to histone release by renal cells. Blocking of histone-mediated damage during transplantation may be beneficial in prevention of renal injury.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2023 van Smaalen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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