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Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy
Aristolochic acid nephropathy (AAN) is characterized by acute proximal tubule necrosis and immune cell infiltration, contributing to the global burden of chronic kidney disease and urothelial cancer. Although the proximal tubule has been defined as the primary target of aristolochic acids I (AAI), t...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9462482/ https://www.ncbi.nlm.nih.gov/pubmed/35852860 http://dx.doi.org/10.1172/jci.insight.157360 |
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author | Chen, Jiayun Luo, Piao Wang, Chen Yang, Chuanbin Bai, Yunmeng He, Xueling Zhang, Qian Zhang, Junzhe Yang, Jing Wang, Shuang Wang, Jigang |
author_facet | Chen, Jiayun Luo, Piao Wang, Chen Yang, Chuanbin Bai, Yunmeng He, Xueling Zhang, Qian Zhang, Junzhe Yang, Jing Wang, Shuang Wang, Jigang |
author_sort | Chen, Jiayun |
collection | PubMed |
description | Aristolochic acid nephropathy (AAN) is characterized by acute proximal tubule necrosis and immune cell infiltration, contributing to the global burden of chronic kidney disease and urothelial cancer. Although the proximal tubule has been defined as the primary target of aristolochic acids I (AAI), the mechanistic underpinning of gross renal deterioration caused by AAI has not been explicitly explained, prohibiting effective therapeutic intervention. To this point, we employed integrated single-cell RNA-Seq, bulk RNA-Seq, and mass spectrometry–based proteomics to analyze the mouse kidney after acute AAI exposure. Our results reveal a dramatic reduction of proximal tubule epithelial cells, associated with apoptotic and inflammatory pathways, indicating permanent damage beyond repair. We found the enriched development pathways in other nephron segments, suggesting activation of reparative programs triggered by AAI. The divergent response may be attributed to the segment-specific distribution of organic anion channels along the nephron, including OAT1 and OAT3. Moreover, we observed dramatic activation and recruitment of cytotoxic T and macrophage M1 cells, highlighting inflammation as a principal contributor to permanent renal injury. Ligand-receptor pairing revealed that critical intercellular crosstalk underpins damage-induced activation of immune cells. These results provide potentially novel insight into the AAI-induced kidney injury and point out possible pathways for future therapeutic intervention. |
format | Online Article Text |
id | pubmed-9462482 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
spelling | pubmed-94624822022-09-13 Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy Chen, Jiayun Luo, Piao Wang, Chen Yang, Chuanbin Bai, Yunmeng He, Xueling Zhang, Qian Zhang, Junzhe Yang, Jing Wang, Shuang Wang, Jigang JCI Insight Research Article Aristolochic acid nephropathy (AAN) is characterized by acute proximal tubule necrosis and immune cell infiltration, contributing to the global burden of chronic kidney disease and urothelial cancer. Although the proximal tubule has been defined as the primary target of aristolochic acids I (AAI), the mechanistic underpinning of gross renal deterioration caused by AAI has not been explicitly explained, prohibiting effective therapeutic intervention. To this point, we employed integrated single-cell RNA-Seq, bulk RNA-Seq, and mass spectrometry–based proteomics to analyze the mouse kidney after acute AAI exposure. Our results reveal a dramatic reduction of proximal tubule epithelial cells, associated with apoptotic and inflammatory pathways, indicating permanent damage beyond repair. We found the enriched development pathways in other nephron segments, suggesting activation of reparative programs triggered by AAI. The divergent response may be attributed to the segment-specific distribution of organic anion channels along the nephron, including OAT1 and OAT3. Moreover, we observed dramatic activation and recruitment of cytotoxic T and macrophage M1 cells, highlighting inflammation as a principal contributor to permanent renal injury. Ligand-receptor pairing revealed that critical intercellular crosstalk underpins damage-induced activation of immune cells. These results provide potentially novel insight into the AAI-induced kidney injury and point out possible pathways for future therapeutic intervention. American Society for Clinical Investigation 2022-08-22 /pmc/articles/PMC9462482/ /pubmed/35852860 http://dx.doi.org/10.1172/jci.insight.157360 Text en © 2022 Chen et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Chen, Jiayun Luo, Piao Wang, Chen Yang, Chuanbin Bai, Yunmeng He, Xueling Zhang, Qian Zhang, Junzhe Yang, Jing Wang, Shuang Wang, Jigang Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy |
title | Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy |
title_full | Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy |
title_fullStr | Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy |
title_full_unstemmed | Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy |
title_short | Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy |
title_sort | integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9462482/ https://www.ncbi.nlm.nih.gov/pubmed/35852860 http://dx.doi.org/10.1172/jci.insight.157360 |
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