Dis Model Mech. 2016 Jun 1; 9(6): 633–645.
doi: 10.1242/dmm.024455
PMCID: PMC4920150
PMID: 27125278
Histone lysine crotonylation during acute kidney injury in mice
Olga Ruiz-Andres,1,2,3 Maria Dolores Sanchez-Niño et al.
ABSTRACT
Acute
kidney injury (AKI) is a potentially lethal condition for which no
therapy is available beyond replacement of renal function.
Post-translational histone modifications modulate gene expression and
kidney injury.
Histone crotonylation is a recently described
post-translational modification.
We hypothesized that histone
crotonylation might modulate kidney injury.
Histone crotonylation was
studied in cultured murine proximal tubular cells and in kidneys from
mice with AKI induced by folic acid or cisplatin.
Histone lysine
crotonylation was observed in tubular cells from healthy murine and
human kidney tissue.
Kidney tissue histone crotonylation increased
during AKI.
This was reproduced by exposure to the protein TWEAK in
cultured tubular cells.
Specifically, ChIP-seq revealed enrichment of
histone crotonylation at the genes encoding the mitochondrial biogenesis
regulator PGC-1α and the sirtuin-3 decrotonylase in both
TWEAK-stimulated tubular cells and in AKI kidney tissue.
To assess the
role of crotonylation in kidney injury, crotonate was used to increase
histone crotonylation in cultured tubular cells or in the kidneys in vivo.
Crotonate increased the expression of PGC-1α and sirtuin-3, and
decreased CCL2 expression in cultured tubular cells and healthy kidneys.
Systemic crotonate administration protected from experimental AKI,
preventing the decrease in renal function and in kidney PGC-1α and
sirtuin-3 levels as well as the increase in CCL2 expression.
For the
first time, we have identified factors such as cell stress and crotonate
availability that increase histone crotonylation in vivo. Overall, increasing histone crotonylation might have a beneficial effect on AKI. This is the first observation of the in vivo potential of the therapeutic manipulation of histone crotonylation in a disease state.
KEY WORDS: Acute kidney injury, Epigenetics, Histone, Inflammation, Tubular cell
Post-translational modifications (PTMs) are changes to proteins or peptides that are catalyzed by enzymes after completion of ribosomal translation and it generally have a positive impact on peptide activity. Post-translational Modification
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