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Regeneration after acute kidney injury requires PTIP-mediated epigenetic modifications
Abdul Soofi, … , Ann M. Laszczyk, Gregory R. Dressler
Abdul Soofi, … , Ann M. Laszczyk, Gregory R. Dressler
Published January 9, 2020
Citation Information: JCI Insight. 2020;5(3):e130204. https://doi.org/10.1172/jci.insight.130204.
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Research Article Nephrology

Regeneration after acute kidney injury requires PTIP-mediated epigenetic modifications

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Abstract

A terminally differentiated cellular phenotype is thought to be maintained, at least in part, by both active and repressive histone marks. However, it is unclear whether regenerating cells after injury need to replicate such epigenetic marks to recover. To test whether renal epithelial cell regeneration is dependent on histone H3K4 methylation, we generated a mouse model that deleted the Paxip1 gene in mature renal proximal tubules. Paxip1 encodes PTIP, an essential protein in the Mll3/4 histone H3K4 methyltransferase complex. Mice with PTIP deletions in the adult kidney proximal tubules were viable and fertile. Upon acute kidney injury, such mice failed to regenerate damaged tubules, leading to scarring and interstitial fibrosis. The inability to repair damage was likely due to a failure to reenter mitosis and reactivate regulatory genes such as Sox9. PTIP deletion reduced histone H3K4 methylation in uninjured adult kidneys but did not significantly affect function or the expression of epithelial specific markers. Strikingly, cell lineage tracing revealed that surviving PTIP mutant cells could alter their phenotype and lose epithelial markers. These data demonstrate that PTIP and associated MLL3/4-mediated histone methylation are needed for regenerating proximal tubules and to maintain or reestablish the cellular epithelial phenotype.

Authors

Abdul Soofi, Ana P. Kutschat, Mohammad Azam, Ann M. Laszczyk, Gregory R. Dressler

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Figure 5

Inhibition of Sox9 activation and cell proliferation in PTIP– proximal tubules after AKI.

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Inhibition of Sox9 activation and cell proliferation in PTIP– proximal t...
(A and B) Cell proliferation was assayed by ki67 immunostaining (green) at 2 days after AKI in PTIP+ (A) and PTIP– (B) kidneys, both costained for αSMA (red). (C) Quantitation of data collected from 3 independent animals and expressed as number of ki67+ cells per low-powered field. (D and E) Immunostaining for Sox9 (green) and αSMA (red) in PTIP+ kidneys (D), or in or PTIP– (E) kidney sections taken 2 days after AKI. (F) Quantitation of 5 sections per animal from 3 independent mice. Note significant numbers of Sox9+ cells in PTIP+ kidneys at 2 days, indicating regeneration, whereas PTIP– kidneys had few, if any, Sox9+ cells 2 days after AKI. *P < 0.001 by 2-way ANOVA.

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