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FOXM1 drives proximal tubule proliferation during repair from acute ischemic kidney injury
Monica Chang-Panesso, … , Akio Kobayashi, Benjamin D. Humphreys
Monica Chang-Panesso, … , Akio Kobayashi, Benjamin D. Humphreys
Published November 11, 2019
Citation Information: J Clin Invest. 2019;129(12):5501-5517. https://doi.org/10.1172/JCI125519.
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Research Article Nephrology Stem cells

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

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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.

Authors

Monica Chang-Panesso, Farid F. Kadyrov, Matthew Lalli, Haojia Wu, Shiyo Ikeda, Eirini Kefaloyianni, Mai M. Abdelmageed, Andreas Herrlich, Akio Kobayashi, Benjamin D. Humphreys

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Figure 8

Foxm1 is expressed after kidney injury in mouse and human.

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Foxm1 is expressed after kidney injury in mouse and human.
(A) mRNA exp...
(A) mRNA expression of Foxm1 and its downstream targets after injury. (B) ISH in uninjured and injured mouse kidneys sections showing increased expression in the outer segment of the outer medulla at day 2 and significant downregulation at day 14. Scale bars: 500 μM (upper panels); 50 μM (lower panels). (C) ISH in human samples from uninjured and injured kidney showing absent FOXM1 expression in the uninjured kidney and expression in cells from injured tubules. Scale bars: 200 μM (upper panels); 50 μM (lower panels). For A and B, n = 3–4 mice per time point. For C, n = 1 for each condition. ***P < 0.001; ****P < 0.0001, 2-way ANOVA with post hoc Dunnett’s multiple comparisons test.
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