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Heparin Attenuates Histone-Mediated Cytotoxicity in Septic Acute Kidney Injury
Histones are considered potential risk factors that contribute to the development of septic acute kidney injury (SAKI) by inducing apoptosis and inflammation. This study aimed to explore the protective effects of heparin on septic acute kidney injury through the neutralization of extracellular histo...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738632/ https://www.ncbi.nlm.nih.gov/pubmed/33344474 http://dx.doi.org/10.3389/fmed.2020.586652 |
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author | Wang, Ziyi Wang, Lijun Cao, Chao Jin, Heng Zhang, Yan Liu, Yancun Gao, Yulei Liang, Xue Li, Guangping Shou, Songtao |
author_facet | Wang, Ziyi Wang, Lijun Cao, Chao Jin, Heng Zhang, Yan Liu, Yancun Gao, Yulei Liang, Xue Li, Guangping Shou, Songtao |
author_sort | Wang, Ziyi |
collection | PubMed |
description | Histones are considered potential risk factors that contribute to the development of septic acute kidney injury (SAKI) by inducing apoptosis and inflammation. This study aimed to explore the protective effects of heparin on septic acute kidney injury through the neutralization of extracellular histones (EH) and to uncover the underlying mechanism. C57BL mice (16 each) were randomly divided into the sham group, the sepsis group (established by cecal ligation and puncture operation, CLP), and the heparin intervention group. Mice in the heparin intervention group received a subcutaneous injection of unfractionated heparin (0.03 IU/g) 4 h after CLP. At 6 h after the operation, nine mice from each group were sacrificed by the removal of the eyeballs to harvest blood samples; the upper half of the right kidney was used as the study sample. Mice renal tubular epithelial cells cultivated in six-well plates were equally divided into five groups. We cultured cells treated with either histone (40 U), histone (40 U) + heparin (25 IU/ml), histone(40U) + lipopolysaccharides (LPS; 10 μg/ml), or histone (40 U) + LPS (10 μg/ml) + heparin (25 IU/ml) for 6 h. For the histone + heparin group and the histone + LPS + heparin group, histone (and LPS) were treated with heparin simultaneously. Mice in the heparin intervention group showed decreased levels of EH4, neutrophil gelatinase-associated lipocalin (NAGL), kidney injury molecule-1 (KIM-1), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 in the blood serum, longer average 72-h survival rate, significantly decreased kidney tissue edema, and a clearer glomerular structure coupled with decreased protein and mRNA expression levels of kidney apoptosis-related proteins (cleaved Caspase-3/Caspase-3 and Bax/Bcl-2) compared with those in the sepsis group at 6 h after CLP (P < 0.05). Meanwhile, cells in the heparin intervention group exhibited lower expression levels of serum EH4 and inflammatory cytokines, a lower apoptosis rate, and decreased expression of apoptosis-related proteins, both at protein and mRNA levels, than those in the histone-stimulated group at 6 h after stimulation (P < 0.05). Heparin may alleviate apoptosis and inflammation through the neutralization of histones, thus playing a protective role against septic acute kidney injury. |
format | Online Article Text |
id | pubmed-7738632 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-77386322020-12-17 Heparin Attenuates Histone-Mediated Cytotoxicity in Septic Acute Kidney Injury Wang, Ziyi Wang, Lijun Cao, Chao Jin, Heng Zhang, Yan Liu, Yancun Gao, Yulei Liang, Xue Li, Guangping Shou, Songtao Front Med (Lausanne) Medicine Histones are considered potential risk factors that contribute to the development of septic acute kidney injury (SAKI) by inducing apoptosis and inflammation. This study aimed to explore the protective effects of heparin on septic acute kidney injury through the neutralization of extracellular histones (EH) and to uncover the underlying mechanism. C57BL mice (16 each) were randomly divided into the sham group, the sepsis group (established by cecal ligation and puncture operation, CLP), and the heparin intervention group. Mice in the heparin intervention group received a subcutaneous injection of unfractionated heparin (0.03 IU/g) 4 h after CLP. At 6 h after the operation, nine mice from each group were sacrificed by the removal of the eyeballs to harvest blood samples; the upper half of the right kidney was used as the study sample. Mice renal tubular epithelial cells cultivated in six-well plates were equally divided into five groups. We cultured cells treated with either histone (40 U), histone (40 U) + heparin (25 IU/ml), histone(40U) + lipopolysaccharides (LPS; 10 μg/ml), or histone (40 U) + LPS (10 μg/ml) + heparin (25 IU/ml) for 6 h. For the histone + heparin group and the histone + LPS + heparin group, histone (and LPS) were treated with heparin simultaneously. Mice in the heparin intervention group showed decreased levels of EH4, neutrophil gelatinase-associated lipocalin (NAGL), kidney injury molecule-1 (KIM-1), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 in the blood serum, longer average 72-h survival rate, significantly decreased kidney tissue edema, and a clearer glomerular structure coupled with decreased protein and mRNA expression levels of kidney apoptosis-related proteins (cleaved Caspase-3/Caspase-3 and Bax/Bcl-2) compared with those in the sepsis group at 6 h after CLP (P < 0.05). Meanwhile, cells in the heparin intervention group exhibited lower expression levels of serum EH4 and inflammatory cytokines, a lower apoptosis rate, and decreased expression of apoptosis-related proteins, both at protein and mRNA levels, than those in the histone-stimulated group at 6 h after stimulation (P < 0.05). Heparin may alleviate apoptosis and inflammation through the neutralization of histones, thus playing a protective role against septic acute kidney injury. Frontiers Media S.A. 2020-12-02 /pmc/articles/PMC7738632/ /pubmed/33344474 http://dx.doi.org/10.3389/fmed.2020.586652 Text en Copyright © 2020 Wang, Wang, Cao, Jin, Zhang, Liu, Gao, Liang, Li and Shou. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Medicine Wang, Ziyi Wang, Lijun Cao, Chao Jin, Heng Zhang, Yan Liu, Yancun Gao, Yulei Liang, Xue Li, Guangping Shou, Songtao Heparin Attenuates Histone-Mediated Cytotoxicity in Septic Acute Kidney Injury |
title | Heparin Attenuates Histone-Mediated Cytotoxicity in Septic Acute Kidney Injury |
title_full | Heparin Attenuates Histone-Mediated Cytotoxicity in Septic Acute Kidney Injury |
title_fullStr | Heparin Attenuates Histone-Mediated Cytotoxicity in Septic Acute Kidney Injury |
title_full_unstemmed | Heparin Attenuates Histone-Mediated Cytotoxicity in Septic Acute Kidney Injury |
title_short | Heparin Attenuates Histone-Mediated Cytotoxicity in Septic Acute Kidney Injury |
title_sort | heparin attenuates histone-mediated cytotoxicity in septic acute kidney injury |
topic | Medicine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738632/ https://www.ncbi.nlm.nih.gov/pubmed/33344474 http://dx.doi.org/10.3389/fmed.2020.586652 |
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