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Global transcriptomic changes in glomerular endothelial cells in mice with podocyte depletion and glomerulosclerosis

Podocytes are a key component of the glomerular filtration barrier, and its dysfunction and eventual loss drive glomerular disease progression. Recent research has demonstrated the importance of podocyte cross-talk with other glomerular cells, such as glomerular endothelial cells (GECs), in both glo...

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Autores principales: Fu, Jia, Yi, Zhengzi, Cai, Minchao, Yuan, Weijie, Zhang, Weijia, Lee, Kyung, He, John Cijiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270962/
https://www.ncbi.nlm.nih.gov/pubmed/34244474
http://dx.doi.org/10.1038/s41419-021-03951-x
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author Fu, Jia
Yi, Zhengzi
Cai, Minchao
Yuan, Weijie
Zhang, Weijia
Lee, Kyung
He, John Cijiang
author_facet Fu, Jia
Yi, Zhengzi
Cai, Minchao
Yuan, Weijie
Zhang, Weijia
Lee, Kyung
He, John Cijiang
author_sort Fu, Jia
collection PubMed
description Podocytes are a key component of the glomerular filtration barrier, and its dysfunction and eventual loss drive glomerular disease progression. Recent research has demonstrated the importance of podocyte cross-talk with other glomerular cells, such as glomerular endothelial cells (GECs), in both glomerular homeostasis and in disease settings. However, how GECs are affected globally by podocyte injury and loss in disease settings remains unclear. Therefore, to characterize the molecular changes occurring in GECs in response to the podocyte loss, we performed the transcriptomic profiling of isolated GECs after diphtheria toxin (DT)-mediated podocyte depletion in transgenic mice with podocyte-specific human DT receptor and endothelial-specific enhanced yellow fluorescent protein (EYFP) expression. DT administration led to nearly 40% of podocyte loss with the development of glomerulosclerosis. Differential gene expression analysis of isolated GECs in the diseased mice showed significant changes in pathways related to cell adhesion and actin cytoskeleton, proliferation, and angiogenesis, as well as apoptosis and cell death. However, quantification of EYFP + GECs indicated that there was a reduction in GECs in the diseased mice, suggesting that despite the ongoing proliferation, the concomitant injury and the activation of cell death program results in their overall net loss. The upstream regulator analysis strongly indicated the involvement of p53, TGF-β1, and TNF-α as key mediators of the molecular changes occurring in GECs in the diseased mice. Our findings demonstrate significant molecular changes in GECs as a secondary consequence of podocyte loss and provide a valuable resource for further in-depth analysis of potential glomerular cross-talk mediators.
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spelling pubmed-82709622021-07-23 Global transcriptomic changes in glomerular endothelial cells in mice with podocyte depletion and glomerulosclerosis Fu, Jia Yi, Zhengzi Cai, Minchao Yuan, Weijie Zhang, Weijia Lee, Kyung He, John Cijiang Cell Death Dis Article Podocytes are a key component of the glomerular filtration barrier, and its dysfunction and eventual loss drive glomerular disease progression. Recent research has demonstrated the importance of podocyte cross-talk with other glomerular cells, such as glomerular endothelial cells (GECs), in both glomerular homeostasis and in disease settings. However, how GECs are affected globally by podocyte injury and loss in disease settings remains unclear. Therefore, to characterize the molecular changes occurring in GECs in response to the podocyte loss, we performed the transcriptomic profiling of isolated GECs after diphtheria toxin (DT)-mediated podocyte depletion in transgenic mice with podocyte-specific human DT receptor and endothelial-specific enhanced yellow fluorescent protein (EYFP) expression. DT administration led to nearly 40% of podocyte loss with the development of glomerulosclerosis. Differential gene expression analysis of isolated GECs in the diseased mice showed significant changes in pathways related to cell adhesion and actin cytoskeleton, proliferation, and angiogenesis, as well as apoptosis and cell death. However, quantification of EYFP + GECs indicated that there was a reduction in GECs in the diseased mice, suggesting that despite the ongoing proliferation, the concomitant injury and the activation of cell death program results in their overall net loss. The upstream regulator analysis strongly indicated the involvement of p53, TGF-β1, and TNF-α as key mediators of the molecular changes occurring in GECs in the diseased mice. Our findings demonstrate significant molecular changes in GECs as a secondary consequence of podocyte loss and provide a valuable resource for further in-depth analysis of potential glomerular cross-talk mediators. Nature Publishing Group UK 2021-07-09 /pmc/articles/PMC8270962/ /pubmed/34244474 http://dx.doi.org/10.1038/s41419-021-03951-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Fu, Jia
Yi, Zhengzi
Cai, Minchao
Yuan, Weijie
Zhang, Weijia
Lee, Kyung
He, John Cijiang
Global transcriptomic changes in glomerular endothelial cells in mice with podocyte depletion and glomerulosclerosis
title Global transcriptomic changes in glomerular endothelial cells in mice with podocyte depletion and glomerulosclerosis
title_full Global transcriptomic changes in glomerular endothelial cells in mice with podocyte depletion and glomerulosclerosis
title_fullStr Global transcriptomic changes in glomerular endothelial cells in mice with podocyte depletion and glomerulosclerosis
title_full_unstemmed Global transcriptomic changes in glomerular endothelial cells in mice with podocyte depletion and glomerulosclerosis
title_short Global transcriptomic changes in glomerular endothelial cells in mice with podocyte depletion and glomerulosclerosis
title_sort global transcriptomic changes in glomerular endothelial cells in mice with podocyte depletion and glomerulosclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270962/
https://www.ncbi.nlm.nih.gov/pubmed/34244474
http://dx.doi.org/10.1038/s41419-021-03951-x
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