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

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 10

Foxm1 is downstream of the Egfr pathway in tubular epithelial proliferation.

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Foxm1 is downstream of the Egfr pathway in tubular epithelial prolifera...
(A) mRNA expression for FOXM1 and several of its downstream targets in hRPTECs after treatment with erlotinib. (B) Western blot in lysates of hRPTECs treated with erlotinib versus vehicle. There is complete absence of FOXM1 protein upon inhibition of EGFR with erlotinib, indicating that FOXM1 is downstream of the EGFR pathway. Lack of phosphor-EGFR expression confirms inhibition of EGFR by erlotinib. (C–E) qPCR for Foxm1, Plk1, and Ki67 2 days after IRI in mice of different strains treated with erlotinib and vehicle. For cell culture experiments, n = 3 replicates per group. For in vivo experiments, n = 3–5 mice per group. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, 2-way ANOVA with post hoc Bonferroni’s multiple comparisons test.