Histone lysine crotonylation during acute kidney injury in mice
EntityUAM. Departamento de Anatomía Patológica; UAM. Departamento de Medicina; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)
PublisherThe Company of Biologists Ltd.
10.1242/dmm.024455DMM. Disease Models & Mechanisms 9 (2016): 633-645
ISSN1754-8403 (print); 1754-8411 (online)
Funded byThis work was supported by the Instituto de Salud Carlos III (ISCIII) [grant numbers PI13/00047, PIE13/00051, PI14/00386, PI15/00298, CP12/03262, CP14/00133, RETIC REDinREN RD12/0021]; the European Regional Development Funds [Fondo Europeo de DesarrolloRegional (FEDER)]; European Uremic Toxin (EUTox) Work Group of the ESAO; the Sociedad Española de Nefrologia (SEN) [9749/002]; Comunidad de Madrid (CIFRA) [grant number S2010/BMD-2378]; and Fundación Renal Iñigo Álvarez de Toledo (FRIAT) [9749/001]. Salary support was provided by ISCIII Miguel Servet MS12/03262 and MS14/00133 to A.B.S. and M.D.S.-N., MECD to O.R.-A. and programa Intensificación Actividad Investigadora (ISCIII/Agencia Laı́n-Entralgo/CM) to A.O. IIS-FJD Biobank RD09/0076/00101
ProjectComunidad de Madrid. S2010/BMD-2378/CIFRA
SubjectsAcute kidney injury; Epigenetics; Histone; Inflammation; Tubular cell; Medicina
Acute kidney injury (AKI) is a potentially lethal condition for which no therapy is available beyond replacement of renal function. Posttranslational histone modifications modulate gene expression and kidney injury. Histone crotonylation is a recently described posttranslational 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 observedintubularcells from healthy murine and human kidney tissue. Kidney tissue histone crotonylation increased during AKI. This was reproducedbyexposure tothe protein TWEAK incultured 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.
Google Scholar:Ruíz Andrés, Olga - Sanchez-Niño, Maria Dolores - Cannata, Pablo - Ruiz-Ortega, Marta - Egido, Jesús - Ortiz, Alberto - Sanz, Ana Belén
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