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

2019/11/10 by Monica Chang-Panesso, Farid F. Kadyrov, Matthew Lalli +9 · 161 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Acute kidney injury #Autophagy in Disease and Therapy #Biology #Cancer research #Cell biology #Endocrinology #FOXM1 #FOXO transcription factor regulation #Gene #Genetics #Immunohistochemistry #Immunology #Internal medicine #Kidney #Medicine #Progenitor cell #Renal and related cancers #Stem cell #Transcription factor #Tubule #Vimentin

paper · pdf · doi:10.1172/jci125519

published in Journal of Clinical Investigation 129(12), 5501-5517 (American Society for Clinical Investigation)

openalex publication_date 2019/11/10 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01

Abstract

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.

Citations

• Kidney injury molecule–1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells

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