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 December 2, 2019; First 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

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 1

Kim1-GCE mouse model.

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Kim1-GCE mouse model. (A) Kim1-GCE was crossed to the Rosa26tdTomato re...
(A) Kim1-GCE was crossed to the Rosa26tdTomato reporter mouse to allow permanent labeling of injured tubular epithelial cells upon tamoxifen-mediated recombination. (B) Uni-IRI was performed to validate the mouse model with kidneys harvested at day 3 and day 14 after injury. (C) Immunofluorescent staining showing endogenous tdTomato expression in the outer segment of the outer medulla at day 3 with increased expression at day 14. There is absence of tdTomato expression in the contralateral kidney after tamoxifen administration indicating no leaky expression. (D) Immunostaining with KIM1 antibody showing coexpression with tdTomato-labeled cells in Kim1-GCE heterozygous mice. There is absence of KIM1 expression in Kim1-GCE homozygous mice, as expected since this a knockin to the ATG site. (E) Western blot for KIM1 showing half the amount of protein expressed in Kim1-GCE heterozygous as compared with WT mice and absence of KIM1 protein in Kim1-GCE homozygous consistent with immunofluorescent staining. (F) Immunostaining showing examples of TP, TN, and FN for determination of sensitivity and specificity for the mouse model. n= 3–4 mice. Scale bars: 500 μM (C); 20 μM (D and F).