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Epithelial and Endothelial Adhesion of Immune Cells Is Enhanced by Cardiotonic Steroid Signaling Through Na(+)/K(+)‐ATPase‐α‐1
BACKGROUND: Recent studies have highlighted a critical role for a group of natriuretic hormones, cardiotonic steroid (CTS), in mediating renal inflammation and fibrosis associated with volume expanded settings, such as chronic kidney disease. Immune cell adhesion is a critical step in the inflammato...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033897/ https://www.ncbi.nlm.nih.gov/pubmed/32013704 http://dx.doi.org/10.1161/JAHA.119.013933 |
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author | Khalaf, Fatimah K. Tassavvor, Iman Mohamed, Amal Chen, Yiliang Malhotra, Deepak Xie, Zijian Tian, Jiang Haller, Steven T. Westfall, Kristen Tang, W. H. Wilson Kennedy, David J. |
author_facet | Khalaf, Fatimah K. Tassavvor, Iman Mohamed, Amal Chen, Yiliang Malhotra, Deepak Xie, Zijian Tian, Jiang Haller, Steven T. Westfall, Kristen Tang, W. H. Wilson Kennedy, David J. |
author_sort | Khalaf, Fatimah K. |
collection | PubMed |
description | BACKGROUND: Recent studies have highlighted a critical role for a group of natriuretic hormones, cardiotonic steroid (CTS), in mediating renal inflammation and fibrosis associated with volume expanded settings, such as chronic kidney disease. Immune cell adhesion is a critical step in the inflammatory response; however, little is currently understood about the potential regulatory role of CTS signaling in this setting. Herein, we tested the hypothesis that CTS signaling through Na(+)/K(+)‐ATPase α‐1 (NKA α‐1) enhances immune cell recruitment and adhesion to renal epithelium that ultimately advance renal inflammation. METHODS AND RESULTS: We demonstrate that knockdown of the α‐1 isoform of Na/K‐ATPase causes a reduction in CTS‐induced macrophage infiltration in renal tissue as well reduces the accumulation of immune cells in the peritoneal cavity in vivo. Next, using functional adhesion assay, we demonstrate that CTS‐induced increases in the adhesion of macrophages to renal epithelial cells were significantly diminished after reduction of NKA α‐1 in either macrophages or renal epithelial cells as well after inhibition of NKA α‐1‐Src signaling cascade with a specific peptide inhibitor, pNaKtide in vitro. Finally, CTS‐induced expression of adhesion markers in both endothelial and immune cells was significantly inhibited in an NKA α‐1‐Src signaling dependent manner in vitro. CONCLUSIONS: These findings suggest that CTS potentiates immune cell migration and adhesion to renal epithelium through an NKA α‐1–dependent mechanism; our new findings suggest that pharmacological inhibition of this feed‐forward loop may be useful in the treatment of renal inflammation associated with renal disease. |
format | Online Article Text |
id | pubmed-7033897 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-70338972020-02-27 Epithelial and Endothelial Adhesion of Immune Cells Is Enhanced by Cardiotonic Steroid Signaling Through Na(+)/K(+)‐ATPase‐α‐1 Khalaf, Fatimah K. Tassavvor, Iman Mohamed, Amal Chen, Yiliang Malhotra, Deepak Xie, Zijian Tian, Jiang Haller, Steven T. Westfall, Kristen Tang, W. H. Wilson Kennedy, David J. J Am Heart Assoc Original Research BACKGROUND: Recent studies have highlighted a critical role for a group of natriuretic hormones, cardiotonic steroid (CTS), in mediating renal inflammation and fibrosis associated with volume expanded settings, such as chronic kidney disease. Immune cell adhesion is a critical step in the inflammatory response; however, little is currently understood about the potential regulatory role of CTS signaling in this setting. Herein, we tested the hypothesis that CTS signaling through Na(+)/K(+)‐ATPase α‐1 (NKA α‐1) enhances immune cell recruitment and adhesion to renal epithelium that ultimately advance renal inflammation. METHODS AND RESULTS: We demonstrate that knockdown of the α‐1 isoform of Na/K‐ATPase causes a reduction in CTS‐induced macrophage infiltration in renal tissue as well reduces the accumulation of immune cells in the peritoneal cavity in vivo. Next, using functional adhesion assay, we demonstrate that CTS‐induced increases in the adhesion of macrophages to renal epithelial cells were significantly diminished after reduction of NKA α‐1 in either macrophages or renal epithelial cells as well after inhibition of NKA α‐1‐Src signaling cascade with a specific peptide inhibitor, pNaKtide in vitro. Finally, CTS‐induced expression of adhesion markers in both endothelial and immune cells was significantly inhibited in an NKA α‐1‐Src signaling dependent manner in vitro. CONCLUSIONS: These findings suggest that CTS potentiates immune cell migration and adhesion to renal epithelium through an NKA α‐1–dependent mechanism; our new findings suggest that pharmacological inhibition of this feed‐forward loop may be useful in the treatment of renal inflammation associated with renal disease. John Wiley and Sons Inc. 2020-01-30 /pmc/articles/PMC7033897/ /pubmed/32013704 http://dx.doi.org/10.1161/JAHA.119.013933 Text en © 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Research Khalaf, Fatimah K. Tassavvor, Iman Mohamed, Amal Chen, Yiliang Malhotra, Deepak Xie, Zijian Tian, Jiang Haller, Steven T. Westfall, Kristen Tang, W. H. Wilson Kennedy, David J. Epithelial and Endothelial Adhesion of Immune Cells Is Enhanced by Cardiotonic Steroid Signaling Through Na(+)/K(+)‐ATPase‐α‐1 |
title | Epithelial and Endothelial Adhesion of Immune Cells Is Enhanced by Cardiotonic Steroid Signaling Through Na(+)/K(+)‐ATPase‐α‐1 |
title_full | Epithelial and Endothelial Adhesion of Immune Cells Is Enhanced by Cardiotonic Steroid Signaling Through Na(+)/K(+)‐ATPase‐α‐1 |
title_fullStr | Epithelial and Endothelial Adhesion of Immune Cells Is Enhanced by Cardiotonic Steroid Signaling Through Na(+)/K(+)‐ATPase‐α‐1 |
title_full_unstemmed | Epithelial and Endothelial Adhesion of Immune Cells Is Enhanced by Cardiotonic Steroid Signaling Through Na(+)/K(+)‐ATPase‐α‐1 |
title_short | Epithelial and Endothelial Adhesion of Immune Cells Is Enhanced by Cardiotonic Steroid Signaling Through Na(+)/K(+)‐ATPase‐α‐1 |
title_sort | epithelial and endothelial adhesion of immune cells is enhanced by cardiotonic steroid signaling through na(+)/k(+)‐atpase‐α‐1 |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033897/ https://www.ncbi.nlm.nih.gov/pubmed/32013704 http://dx.doi.org/10.1161/JAHA.119.013933 |
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