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ResearchIn-Press PreviewCell biologyNephrology Open Access | 10.1172/jci.insight.157360

Integrated single-cell transcriptomics and proteomics reveal cellular-specific response and microenvironment remodeling in aristolochic acid nephropathy

Jiayun Chen,1 Piao Luo,1 Chen Wang,1 Chuanbin Yang,2 Yunmeng Bai,2 Xueling He,1 Qian Zhang,1 Junzhe Zhang,1 Jing Yang,2 Shuang Wang,2 and Jigang Wang1

1Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China

2Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China

Find articles by Chen, J. in: JCI | PubMed | Google Scholar |

1Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China

2Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China

Find articles by Luo, P. in: JCI | PubMed | Google Scholar

1Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China

2Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China

Find articles by Wang, C. in: JCI | PubMed | Google Scholar

1Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China

2Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China

Find articles by Yang, C. in: JCI | PubMed | Google Scholar

1Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China

2Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China

Find articles by Bai, Y. in: JCI | PubMed | Google Scholar

1Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China

2Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China

Find articles by He, X. in: JCI | PubMed | Google Scholar

1Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China

2Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China

Find articles by Zhang, Q. in: JCI | PubMed | Google Scholar

1Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China

2Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China

Find articles by Zhang, J. in: JCI | PubMed | Google Scholar

1Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China

2Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China

Find articles by Yang, J. in: JCI | PubMed | Google Scholar

1Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China

2Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China

Find articles by Wang, S. in: JCI | PubMed | Google Scholar |

1Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China

2Department of Geriatrics, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, China

Find articles by Wang, J. in: JCI | PubMed | Google Scholar

Published July 19, 2022 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.157360.
Copyright © 2022, Chen et al. 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/.
Published July 19, 2022 - Version history
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Abstract

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-sequencing, bulk RNA-sequencing, and mass spectrometry-based proteomics to analyze mouse kidney post-acute AAI exposure. Our results revealed 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 anions 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 critical intercellular crosstalk underpins damage-induced activation of immune cells. These results provide novel insight into AAI-induced kidney injury and point out potential pathways for future therapeutic intervention.

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graphical abstract
Supplemental material

View Supplement data1. Integrated scRNA-seq datasets

View Supplement data2. Proximal tubule cell

View Supplement data3. Other segments epithelial

View Supplement data4. T lymphcyte and NK cell

View Supplement data5. Myeloid cell

View Supplement data6. Stromal cell

View Supplement data7. Bulk RNA-seq and Mass spec

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