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Histone lysine crotonylation during acute kidney injury in mice

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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.

No MeSH data available.


TWEAK increases histone crotonylation in kidney tubular cells. Western blotting of histone crotonylation (anti-Kcr) in cultured murine proximal tubular cells stimulated with 100 ng/ml TWEAK. Data from five independent experiments is expressed as the mean±s.e.m. Results are expressed as percentage change of crotonylated histones over control.*P<0.05 vs control (Student's t-test).
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DMM024455F2: TWEAK increases histone crotonylation in kidney tubular cells. Western blotting of histone crotonylation (anti-Kcr) in cultured murine proximal tubular cells stimulated with 100 ng/ml TWEAK. Data from five independent experiments is expressed as the mean±s.e.m. Results are expressed as percentage change of crotonylated histones over control.*P<0.05 vs control (Student's t-test).

Mentions: Next, we explored the hypothesis that inflammatory mediators of AKI could modulate histone crotonylation. TWEAK is a key mediator of AKI that promotes inflammatory responses in cultured tubular cells but has no direct cytotoxicity if used in the absence of other inflammatory mediators (Sanz et al., 2010b; Izquierdo et al., 2012). Hence, we studied the effect of TWEAK on histone crotonylation in kidney cells. TWEAK increased histone crotonylation at 6 and 24 h in cultured tubular cells (Fig. 2). These results suggest that inflammatory cytokines can regulate the histone crotonylation status in kidney cells.Fig. 2.


Histone lysine crotonylation during acute kidney injury in mice
TWEAK increases histone crotonylation in kidney tubular cells. Western blotting of histone crotonylation (anti-Kcr) in cultured murine proximal tubular cells stimulated with 100 ng/ml TWEAK. Data from five independent experiments is expressed as the mean±s.e.m. Results are expressed as percentage change of crotonylated histones over control.*P<0.05 vs control (Student's t-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4920150&req=5

DMM024455F2: TWEAK increases histone crotonylation in kidney tubular cells. Western blotting of histone crotonylation (anti-Kcr) in cultured murine proximal tubular cells stimulated with 100 ng/ml TWEAK. Data from five independent experiments is expressed as the mean±s.e.m. Results are expressed as percentage change of crotonylated histones over control.*P<0.05 vs control (Student's t-test).
Mentions: Next, we explored the hypothesis that inflammatory mediators of AKI could modulate histone crotonylation. TWEAK is a key mediator of AKI that promotes inflammatory responses in cultured tubular cells but has no direct cytotoxicity if used in the absence of other inflammatory mediators (Sanz et al., 2010b; Izquierdo et al., 2012). Hence, we studied the effect of TWEAK on histone crotonylation in kidney cells. TWEAK increased histone crotonylation at 6 and 24 h in cultured tubular cells (Fig. 2). These results suggest that inflammatory cytokines can regulate the histone crotonylation status in kidney cells.Fig. 2.

View Article: PubMed Central - PubMed

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-1&alpha; 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-1&alpha; 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-1&alpha; 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.

No MeSH data available.