Published July 6, 2021 | Published
Journal Article Open

Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury

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Abstract

Acute kidney injury (AKI), commonly caused by ischemia, sepsis, or nephrotoxic insult, is associated with increased mortality and a heightened risk of chronic kidney disease (CKD). AKI results in the dysfunction or death of proximal tubule cells (PTCs), triggering a poorly understood autologous cellular repair program. Defective repair associates with a long-term transition to CKD. We performed a mild-to-moderate ischemia–reperfusion injury (IRI) to model injury responses reflective of kidney injury in a variety of clinical settings, including kidney transplant surgery. Single-nucleus RNA sequencing of genetically labeled injured PTCs at 7-d (“early”) and 28-d (“late”) time points post-IRI identified specific gene and pathway activity in the injury–repair transition. In particular, we identified Vcam1+/Ccl2+ PTCs at a late injury stage distinguished by marked activation of NF-κB–, TNF-, and AP-1–signaling pathways. This population of PTCs showed features of a senescence-associated secretory phenotype but did not exhibit G2/M cell cycle arrest, distinct from other reports of maladaptive PTCs following kidney injury. Fate-mapping experiments identified spatially and temporally distinct origins for these cells. At the cortico-medullary boundary (CMB), where injury initiates, the majority of Vcam1+/Ccl2+ PTCs arose from early replicating PTCs. In contrast, in cortical regions, only a subset of Vcam1+/Ccl2+ PTCs could be traced to early repairing cells, suggesting late-arising sites of secondary PTC injury. Together, these data indicate even moderate IRI is associated with a lasting injury, which spreads from the CMB to cortical regions. Remaining failed-repair PTCs are likely triggers for chronic disease progression.

Copyright and License

This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND)

Acknowledgement

We thank Dr. Jordi van Gestel and Dr. Andrew Ransick for help with the bioinformatics analysis. L.M.S.G. was supported by the German Research Foundation with a postdoctoral scholarship (GE 3179/1-1). P.E.C. was supported by the Swiss National Science Foundation (Grant 167773), by the Gianella Foundation, and by the Balli Foundation. Work in A.P.M.’s laboratory was supported by a ReBuilding The Kidney Partnership grant from the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK107350) and by a ReBuilding The Kidney Program grant (UC2DK126024).

Funding

L.M.S.G. was supported by the German Research Foundation with a postdoctoral scholarship (GE 3179/1-1). P.E.C. was supported by the Swiss National Science Foundation (Grant 167773), by the Gianella Foundation, and by the Balli Foundation. Work in A.P.M.’s laboratory was supported by a ReBuilding The Kidney Partnership grant from the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK107350) and by a ReBuilding The Kidney Program grant (UC2DK126024).

Contributions

.M.S.G., J.L., K.K., P.E.C., and A.P.M. designed research; L.M.S.G.,J.L., K.K., and P.E.C. performed research; L.M.S.G., J.L., P.E.C., and A.P.M. analyzed data;and L.M.S.G. and A.P.M. wrote the paper.

Data Availability

The single-nuclei RNA sequencing data have been deposited in the Gene Expression Omnibus (GEO) database (accession no. GSE171417). All study data are included in the article and/or supporting information. Previously published data were used for this work (https://doi.org/10.1172/jci.insight.123151https://doi.org/10.1038/s42255-020-0238-1).

Conflict of Interest

A.P.M. is a scientific advisor on kidney-related approachesto human disease for Novartis, eGenesis, Iviva, and Trestle Biotherapeutics.

Supplemental Material

Supporting Information:

Appendix (PDF)
Dataset_S01 (XLSX)
Dataset_S02 (XLSX)
Dataset_S03 (XLSX)
Dataset_S04 (XLSX)
Dataset_S05 (XLSX)

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Created:
November 15, 2024
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November 15, 2024