FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury

The proximal tubule has a remarkable capacity for repair after acute injury, but the cellular lineage and molecular mechanisms underlying this repair response are incompletely understood. Here, we developed a Kim1-GFPCreERt2 knockin mouse line (Kim1-GCE) in order to perform genetic lineage tracing o...

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Bibliographic Details
Published in:The Journal of clinical investigation 2019-12, Vol.129 (12), p.5501-5517
Main Authors: Chang-Panesso, Monica, Kadyrov, Farid F, Lalli, Matthew, Wu, Haojia, Ikeda, Shiyo, Kefaloyianni, Eirini, Abdelmageed, Mai M, Herrlich, Andreas, Kobayashi, Akio, Humphreys, Benjamin D
Format: Article
Language:English
Subjects:
Acute Kidney Injury - pathology
Adult
Analysis
Animals
Cell Dedifferentiation
Cell Lineage
Cell Proliferation
Criminal investigation
Disease Models, Animal
Epidermal growth factors
ErbB Receptors - physiology
Female
Forkhead Box Protein M1 - physiology
Humans
Kidney - blood supply
Kidney Tubules, Proximal - pathology
Labels
Male
Mice
Mice, Inbred C57BL
Middle Aged
Reperfusion Injury - pathology
Scientific equipment industry
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Summary:The proximal tubule has a remarkable capacity for repair after acute injury, but the cellular lineage and molecular mechanisms underlying this repair response are incompletely understood. Here, we developed a Kim1-GFPCreERt2 knockin mouse line (Kim1-GCE) in order to perform genetic lineage tracing of dedifferentiated cells while measuring the cellular transcriptome of proximal tubule during repair. Acutely injured genetically labeled clones coexpressed KIM1, VIMENTIN, SOX9, and KI67, indicating a dedifferentiated and proliferative state. Clonal analysis revealed clonal expansion of Kim1+ cells, indicating that acutely injured, dedifferentiated proximal tubule cells, rather than fixed tubular progenitor cells, account for repair. Translational profiling during injury and repair revealed signatures of both successful and unsuccessful maladaptive repair. The transcription factor Foxm1 was induced early in injury, was required for epithelial proliferation in vitro, and was dependent on epidermal growth factor receptor (EGFR) stimulation. In conclusion, dedifferentiated proximal tubule cells effect proximal tubule repair, and we reveal an EGFR/FOXM1-dependent signaling pathway that drives proliferative repair after injury.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI125519