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Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury

BACKGROUND: Acute kidney injury (AKI) occurs frequently in critically ill patients and is associated with adverse outcomes. Cellular mechanisms underlying AKI and kidney cell responses to injury remain incompletely understood. METHODS: We performed single-nuclei transcriptomics, bulk transcriptomics...

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Autores principales: Hinze, Christian, Kocks, Christine, Leiz, Janna, Karaiskos, Nikos, Boltengagen, Anastasiya, Cao, Shuang, Skopnik, Christopher Mark, Klocke, Jan, Hardenberg, Jan-Hendrik, Stockmann, Helena, Gotthardt, Inka, Obermayer, Benedikt, Haghverdi, Laleh, Wyler, Emanuel, Landthaler, Markus, Bachmann, Sebastian, Hocke, Andreas C., Corman, Victor, Busch, Jonas, Schneider, Wolfgang, Himmerkus, Nina, Bleich, Markus, Eckardt, Kai-Uwe, Enghard, Philipp, Rajewsky, Nikolaus, Schmidt-Ott, Kai M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9462075/
https://www.ncbi.nlm.nih.gov/pubmed/36085050
http://dx.doi.org/10.1186/s13073-022-01108-9
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author Hinze, Christian
Kocks, Christine
Leiz, Janna
Karaiskos, Nikos
Boltengagen, Anastasiya
Cao, Shuang
Skopnik, Christopher Mark
Klocke, Jan
Hardenberg, Jan-Hendrik
Stockmann, Helena
Gotthardt, Inka
Obermayer, Benedikt
Haghverdi, Laleh
Wyler, Emanuel
Landthaler, Markus
Bachmann, Sebastian
Hocke, Andreas C.
Corman, Victor
Busch, Jonas
Schneider, Wolfgang
Himmerkus, Nina
Bleich, Markus
Eckardt, Kai-Uwe
Enghard, Philipp
Rajewsky, Nikolaus
Schmidt-Ott, Kai M.
author_facet Hinze, Christian
Kocks, Christine
Leiz, Janna
Karaiskos, Nikos
Boltengagen, Anastasiya
Cao, Shuang
Skopnik, Christopher Mark
Klocke, Jan
Hardenberg, Jan-Hendrik
Stockmann, Helena
Gotthardt, Inka
Obermayer, Benedikt
Haghverdi, Laleh
Wyler, Emanuel
Landthaler, Markus
Bachmann, Sebastian
Hocke, Andreas C.
Corman, Victor
Busch, Jonas
Schneider, Wolfgang
Himmerkus, Nina
Bleich, Markus
Eckardt, Kai-Uwe
Enghard, Philipp
Rajewsky, Nikolaus
Schmidt-Ott, Kai M.
author_sort Hinze, Christian
collection PubMed
description BACKGROUND: Acute kidney injury (AKI) occurs frequently in critically ill patients and is associated with adverse outcomes. Cellular mechanisms underlying AKI and kidney cell responses to injury remain incompletely understood. METHODS: We performed single-nuclei transcriptomics, bulk transcriptomics, molecular imaging studies, and conventional histology on kidney tissues from 8 individuals with severe AKI (stage 2 or 3 according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria). Specimens were obtained within 1–2 h after individuals had succumbed to critical illness associated with respiratory infections, with 4 of 8 individuals diagnosed with COVID-19. Control kidney tissues were obtained post-mortem or after nephrectomy from individuals without AKI. RESULTS: High-depth single cell-resolved gene expression data of human kidneys affected by AKI revealed enrichment of novel injury-associated cell states within the major cell types of the tubular epithelium, in particular in proximal tubules, thick ascending limbs, and distal convoluted tubules. Four distinct, hierarchically interconnected injured cell states were distinguishable and characterized by transcriptome patterns associated with oxidative stress, hypoxia, interferon response, and epithelial-to-mesenchymal transition, respectively. Transcriptome differences between individuals with AKI were driven primarily by the cell type-specific abundance of these four injury subtypes rather than by private molecular responses. AKI-associated changes in gene expression between individuals with and without COVID-19 were similar. CONCLUSIONS: The study provides an extensive resource of the cell type-specific transcriptomic responses associated with critical illness-associated AKI in humans, highlighting recurrent disease-associated signatures and inter-individual heterogeneity. Personalized molecular disease assessment in human AKI may foster the development of tailored therapies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-022-01108-9.
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spelling pubmed-94620752022-09-10 Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury Hinze, Christian Kocks, Christine Leiz, Janna Karaiskos, Nikos Boltengagen, Anastasiya Cao, Shuang Skopnik, Christopher Mark Klocke, Jan Hardenberg, Jan-Hendrik Stockmann, Helena Gotthardt, Inka Obermayer, Benedikt Haghverdi, Laleh Wyler, Emanuel Landthaler, Markus Bachmann, Sebastian Hocke, Andreas C. Corman, Victor Busch, Jonas Schneider, Wolfgang Himmerkus, Nina Bleich, Markus Eckardt, Kai-Uwe Enghard, Philipp Rajewsky, Nikolaus Schmidt-Ott, Kai M. Genome Med Research BACKGROUND: Acute kidney injury (AKI) occurs frequently in critically ill patients and is associated with adverse outcomes. Cellular mechanisms underlying AKI and kidney cell responses to injury remain incompletely understood. METHODS: We performed single-nuclei transcriptomics, bulk transcriptomics, molecular imaging studies, and conventional histology on kidney tissues from 8 individuals with severe AKI (stage 2 or 3 according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria). Specimens were obtained within 1–2 h after individuals had succumbed to critical illness associated with respiratory infections, with 4 of 8 individuals diagnosed with COVID-19. Control kidney tissues were obtained post-mortem or after nephrectomy from individuals without AKI. RESULTS: High-depth single cell-resolved gene expression data of human kidneys affected by AKI revealed enrichment of novel injury-associated cell states within the major cell types of the tubular epithelium, in particular in proximal tubules, thick ascending limbs, and distal convoluted tubules. Four distinct, hierarchically interconnected injured cell states were distinguishable and characterized by transcriptome patterns associated with oxidative stress, hypoxia, interferon response, and epithelial-to-mesenchymal transition, respectively. Transcriptome differences between individuals with AKI were driven primarily by the cell type-specific abundance of these four injury subtypes rather than by private molecular responses. AKI-associated changes in gene expression between individuals with and without COVID-19 were similar. CONCLUSIONS: The study provides an extensive resource of the cell type-specific transcriptomic responses associated with critical illness-associated AKI in humans, highlighting recurrent disease-associated signatures and inter-individual heterogeneity. Personalized molecular disease assessment in human AKI may foster the development of tailored therapies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13073-022-01108-9. BioMed Central 2022-09-09 /pmc/articles/PMC9462075/ /pubmed/36085050 http://dx.doi.org/10.1186/s13073-022-01108-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Hinze, Christian
Kocks, Christine
Leiz, Janna
Karaiskos, Nikos
Boltengagen, Anastasiya
Cao, Shuang
Skopnik, Christopher Mark
Klocke, Jan
Hardenberg, Jan-Hendrik
Stockmann, Helena
Gotthardt, Inka
Obermayer, Benedikt
Haghverdi, Laleh
Wyler, Emanuel
Landthaler, Markus
Bachmann, Sebastian
Hocke, Andreas C.
Corman, Victor
Busch, Jonas
Schneider, Wolfgang
Himmerkus, Nina
Bleich, Markus
Eckardt, Kai-Uwe
Enghard, Philipp
Rajewsky, Nikolaus
Schmidt-Ott, Kai M.
Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury
title Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury
title_full Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury
title_fullStr Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury
title_full_unstemmed Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury
title_short Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury
title_sort single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9462075/
https://www.ncbi.nlm.nih.gov/pubmed/36085050
http://dx.doi.org/10.1186/s13073-022-01108-9
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