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Glomerular endothelial cell heterogeneity in Alport syndrome
Glomerular endothelial cells (GEC) are a crucial component of the glomerular physiology and their damage contributes to the progression of chronic kidney diseases. How GEC affect the pathology of Alport syndrome (AS) however, is unclear. We characterized GEC from wild type (WT) and col4α5 knockout A...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351764/ https://www.ncbi.nlm.nih.gov/pubmed/32651395 http://dx.doi.org/10.1038/s41598-020-67588-0 |
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author | Soloyan, Hasmik Thornton, Matthew Villani, Valentina Khatchadourian, Patrick Cravedi, Paolo Angeletti, Andrea Grubbs, Brendan De Filippo, Roger Perin, Laura Sedrakyan, Sargis |
author_facet | Soloyan, Hasmik Thornton, Matthew Villani, Valentina Khatchadourian, Patrick Cravedi, Paolo Angeletti, Andrea Grubbs, Brendan De Filippo, Roger Perin, Laura Sedrakyan, Sargis |
author_sort | Soloyan, Hasmik |
collection | PubMed |
description | Glomerular endothelial cells (GEC) are a crucial component of the glomerular physiology and their damage contributes to the progression of chronic kidney diseases. How GEC affect the pathology of Alport syndrome (AS) however, is unclear. We characterized GEC from wild type (WT) and col4α5 knockout AS mice, a hereditary disorder characterized by progressive renal failure. We used endothelial-specific Tek-tdTomato reporter mice to isolate GEC by FACS and performed transcriptome analysis on them from WT and AS mice, followed by in vitro functional assays and confocal and intravital imaging studies. Biopsies from patients with chronic kidney disease, including AS were compared with our findings in mice. We identified two subpopulations of GEC (dim(tdT) and bright(tdT)) based on the fluorescence intensity of the Tek(tdT) signal. In AS mice, the bright(tdT) cell number increased and presented differential expression of endothelial markers compared to WT. RNA-seq analysis revealed differences in the immune and metabolic signaling pathways. In AS mice, dim(tdT) and bright(tdT) cells had different expression profiles of matrix-associated genes (Svep1, Itgβ6), metabolic activity (Apom, Pgc1α) and immune modulation (Apelin, Icam1) compared to WT mice. We confirmed a new pro-inflammatory role of Apelin in AS mice and in cultured human GEC. Gene modulations were identified comparable to the biopsies from patients with AS and focal segmental glomerulosclerosis, possibly indicating that the same mechanisms apply to humans. We report the presence of two GEC subpopulations that differ between AS and healthy mice or humans. This finding paves the way to a better understanding of the pathogenic role of GEC in AS progression and could lead to novel therapeutic targets. |
format | Online Article Text |
id | pubmed-7351764 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73517642020-07-14 Glomerular endothelial cell heterogeneity in Alport syndrome Soloyan, Hasmik Thornton, Matthew Villani, Valentina Khatchadourian, Patrick Cravedi, Paolo Angeletti, Andrea Grubbs, Brendan De Filippo, Roger Perin, Laura Sedrakyan, Sargis Sci Rep Article Glomerular endothelial cells (GEC) are a crucial component of the glomerular physiology and their damage contributes to the progression of chronic kidney diseases. How GEC affect the pathology of Alport syndrome (AS) however, is unclear. We characterized GEC from wild type (WT) and col4α5 knockout AS mice, a hereditary disorder characterized by progressive renal failure. We used endothelial-specific Tek-tdTomato reporter mice to isolate GEC by FACS and performed transcriptome analysis on them from WT and AS mice, followed by in vitro functional assays and confocal and intravital imaging studies. Biopsies from patients with chronic kidney disease, including AS were compared with our findings in mice. We identified two subpopulations of GEC (dim(tdT) and bright(tdT)) based on the fluorescence intensity of the Tek(tdT) signal. In AS mice, the bright(tdT) cell number increased and presented differential expression of endothelial markers compared to WT. RNA-seq analysis revealed differences in the immune and metabolic signaling pathways. In AS mice, dim(tdT) and bright(tdT) cells had different expression profiles of matrix-associated genes (Svep1, Itgβ6), metabolic activity (Apom, Pgc1α) and immune modulation (Apelin, Icam1) compared to WT mice. We confirmed a new pro-inflammatory role of Apelin in AS mice and in cultured human GEC. Gene modulations were identified comparable to the biopsies from patients with AS and focal segmental glomerulosclerosis, possibly indicating that the same mechanisms apply to humans. We report the presence of two GEC subpopulations that differ between AS and healthy mice or humans. This finding paves the way to a better understanding of the pathogenic role of GEC in AS progression and could lead to novel therapeutic targets. Nature Publishing Group UK 2020-07-10 /pmc/articles/PMC7351764/ /pubmed/32651395 http://dx.doi.org/10.1038/s41598-020-67588-0 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Soloyan, Hasmik Thornton, Matthew Villani, Valentina Khatchadourian, Patrick Cravedi, Paolo Angeletti, Andrea Grubbs, Brendan De Filippo, Roger Perin, Laura Sedrakyan, Sargis Glomerular endothelial cell heterogeneity in Alport syndrome |
title | Glomerular endothelial cell heterogeneity in Alport syndrome |
title_full | Glomerular endothelial cell heterogeneity in Alport syndrome |
title_fullStr | Glomerular endothelial cell heterogeneity in Alport syndrome |
title_full_unstemmed | Glomerular endothelial cell heterogeneity in Alport syndrome |
title_short | Glomerular endothelial cell heterogeneity in Alport syndrome |
title_sort | glomerular endothelial cell heterogeneity in alport syndrome |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351764/ https://www.ncbi.nlm.nih.gov/pubmed/32651395 http://dx.doi.org/10.1038/s41598-020-67588-0 |
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