{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T14:27:11Z","timestamp":1793111231976,"version":"4.5.0"},"reference-count":70,"publisher":"American Society for Clinical Investigation","issue":"16","license":[{"start":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T00:00:00Z","timestamp":1661126400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Major National Science and Technology Program of China for Innovative Drug","award":["2017ZX09101002-001-001-05"],"award-info":[{"award-number":["2017ZX09101002-001-001-05"]}]},{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["81903588,82074098,81841001"],"award-info":[{"award-number":["81903588,82074098,81841001"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Fundamental Research Funds for the Central Public Welfare Research Institutes","award":["ZXKT18003"],"award-info":[{"award-number":["ZXKT18003"]}]},{"name":"the National Key Research and Development Program of China","award":["2020YFA0908000"],"award-info":[{"award-number":["2020YFA0908000"]}]},{"name":"the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine","award":["ZYYCXTD-C-202002"],"award-info":[{"award-number":["ZYYCXTD-C-202002"]}]},{"name":"National Key R&D Program of China Key projects for international cooperation on science, technology and innovation","award":["2020YFE0205100"],"award-info":[{"award-number":["2020YFE0205100"]}]},{"name":"the Science and Technology Foundation of Shenzhen","award":["JCYJ20210324115800001"],"award-info":[{"award-number":["JCYJ20210324115800001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,22]]},"abstract":"<jats:p>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\u2013based 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.<\/jats:p>","DOI":"10.1172\/jci.insight.157360","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T12:01:23Z","timestamp":1658232083000},"source":"Crossref","is-referenced-by-count":39,"title":["Integrated single-cell transcriptomics and proteomics reveal cellular-specific responses and microenvironment remodeling in aristolochic acid nephropathy"],"prefix":"10.1172","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4244-9570","authenticated-orcid":true,"given":"Jiayun","family":"Chen","sequence":"first","affiliation":[{"name":"Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piao","family":"Luo","sequence":"additional","affiliation":[{"name":"Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Wang","sequence":"additional","affiliation":[{"name":"Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanbin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunmeng","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueling","family":"He","sequence":"additional","affiliation":[{"name":"Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junzhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0170-4395","authenticated-orcid":true,"given":"Shuang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jigang","family":"Wang","sequence":"additional","affiliation":[{"name":"Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China."},{"name":"Department of Geriatrics, Shenzhen People\u2019s Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China."},{"name":"Center for Reproductive Medicine, Dongguan Maternal and Child Health Care Hospital, Southern Medical University, Dongguan, Guangdong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2022,8,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.26310"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.107.014688"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(93)92984-2"},{"issue":"5","key":"B4","first-page":"474","article-title":"Nephropathy after use of Chinese herbs: rapidly progressive interstitial renal fibrosis or renal vasculitis?","volume":"96","author":"Wankowicz","year":"1996","journal-title":"Pol Arch Med Wewn"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2008.129"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1007\/s40264-014-0244-x"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(99)03380-2"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)69079-X"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfn140"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2014.114"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5002714"},{"issue":"2","key":"B12","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1211\/0022357023051","article-title":"Acute nephrotoxicity of aristolochic acids in mice","volume":"56","author":"Sato","year":"2004","journal-title":"J Pharm Pharmacol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1997.35"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S0272-6386(12)80178-8"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-23565-2"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat1699"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar2131"},{"issue":"2","key":"B18","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41576-020-00292-x","article-title":"Deciphering cell-cell interactions and communication from gene expression","volume":"22","author":"Armingol","year":"2021","journal-title":"Nat Rev Genet"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2018.05.010"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15986-3"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2005477117"},{"issue":"9","key":"B22","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.93009","article-title":"Single cell RNA sequencing to dissect the molecular heterogeneity in lupus nephritis","volume":"2","author":"Der","year":"2017","journal-title":"JCI Insight"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13382-0"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08831-9"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2020.105054"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2019.12.004"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2021081150"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1186\/s12882-018-0937-y"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1186\/s12882-018-1122-z"},{"key":"B31","doi-asserted-by":"crossref","DOI":"10.1155\/2016\/2174682","article-title":"Inhibition of macrophage migration inhibitory factor protects against inflammation and matrix deposition in kidney tissues after injury","volume":"2016","author":"Lu","year":"2016","journal-title":"Mediators Inflamm"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-30628-x"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0414-6"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202000949R"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2144"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2018.10.013"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfu230"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.kint.2017.06.030"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016121351"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.32604\/biocell.2007.31.213"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4463"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/path.5775"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2020010052"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.09.023"},{"issue":"4","key":"B46","doi-asserted-by":"crossref","DOI":"10.1096\/fj.202101555RR","article-title":"TIMP2 mediates endoplasmic reticulum stress contributing to sepsis-induced acute kidney injury","volume":"36","author":"Jiang","year":"2022","journal-title":"FASEB J"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1111\/j.1523-1755.2005.00626.x"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abd9738"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/kisup.2014.4"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-019-0110-2"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat5031"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21246-9"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1074"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2016.48"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1177\/0960327111424302"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.2174\/1389200211314060006"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-016-1808-6"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1159\/000142934"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015030261"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1038\/ki.1991.201"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1097\/01.ASN.0000017901.77985F"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty560"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"issue":"3","key":"B64","article-title":"clusterProfiler 4.0: a universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation (Camb)"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.2859"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbq064"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-021-02216-w"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/157360\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T23:30:39Z","timestamp":1779147039000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/157360"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,22]]},"references-count":70,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8,22]]},"published-print":{"date-parts":[[2022,8,22]]}},"alternative-id":["10.1172\/jci.insight.157360"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.157360","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,22]]},"article-number":"e157360"}}