Dataset Information

Epigenetic alterations in acute kidney injury.

ABSTRACT: Acute kidney injury (AKI) is a risk factor for chronic kidney disease and death. Despite progress made in understanding the cellular and molecular basis of AKI pathogenesis there has been no improvement in the high mortality rate from this disease in decades. Epigenetics is one of the most intensively studied fields of biology today and represents a new paradigm for understanding the pathophysiology of disease. Although epigenetics of AKI is a nascent field, the available information already is providing compelling evidence that chromatin biology plays a critical role in this disease. In this article we explore what is known about the contribution of epigenetic mechanisms to the pathophysiology of AKI and how this knowledge already is guiding the development of new diagnostic tools and epigenetic therapies.

SUBMITTER: Bomsztyk K

PROVIDER: S-EPMC3768006 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Epigenetic alterations in acute kidney injury.

Bomsztyk Karol K Denisenko Oleg O

Seminars in nephrology 20130701 4

Acute kidney injury (AKI) is a risk factor for chronic kidney disease and death. Despite progress made in understanding the cellular and molecular basis of AKI pathogenesis there has been no improvement in the high mortality rate from this disease in decades. Epigenetics is one of the most intensively studied fields of biology today and represents a new paradigm for understanding the pathophysiology of disease. Although epigenetics of AKI is a nascent field, the available information already is ...[more]

PMID: 24011575

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Project description:BackgroundAs a consequence of acute kidney injury (AKI), proximal tubular cells hyperrespond to endotoxin (lipopolysaccharide, LPS) by exaggerated renal Tnf-? Production. This LPS hyperresponsiveness is transcriptionally mediated. The epigenetic pathways that control these responses are unknown.Methods/findingsWe applied multiplex chromatin immunoprecipitation platform (Matrix ChIP) to explore epigenetic pathways that underlie endotoxin hyperresponsiveness in the setting of preceding unilateral renal ischemia/reperfusion (I/R) in mouse AKI model. Endotoxin exposure after I/R resulted in enhanced transcription, manifested by hyperresponsive recruitment of RNA polymerase II (Pol II) at the Tnf-? gene. At this locus, LPS but not I/R increased levels of Pol II C-terminal domain (CTD) phosho-serine2 &5 and induced dephosphorylation of the transcription-repressive histone H4 phospho-serine-1. In contrast, I/R but not LPS increased the transcription-permissive histone phosphorylation (H3 phospho-serine-10, H3.3 phospho-serine-31) at the Tnf-? gene. In agreement with these observations, I/R but not LPS increased activity of cognate kinases (Erk1/2, Msk1/2 and Aurora A) at the Tnf-? locus. Cross-talk of histone phosphorylation and acetylation synergize to active gene expression. I/R and LPS increased histone acetylation. (H3K9/14Ac, H4K5/8/12/16Ac, H2KA5Ac, H2BK4/7Ac). Levels of some histone acetyltransferases at this gene (PCAF and MOF) were increased by I/R but not by LPS, while others were induced by either I/R or LPS and exhibited endotoxin hyperresponsive patterns (GCN5, CBP and p300). The adaptor protein 14-3-3 couples histone phosphorylation with acetylation, and tethers chromatin modifiers/transcription elongation factors to target genes. Both I/R and LPS increased levels of 14-3-3 and several chromatin/transcription modifiers (BRD4, BRG1, HP-1? and IKK?) at the Tnf-? gene, all exhibiting endotoxin hyperresponsive recruitment patterns similar to Pol II.ConclusionsOur results suggest that I/R and LPS differentially trigger phosphorylation (Pol II and histone) and acetylation (histone) epigenetic pathways that interact at the Tnf-? gene to generate endotoxin hyperresponse in AKI.

Dataset Information

Epigenetic alterations in acute kidney injury.

Publications

Epigenetic alterations in acute kidney injury.

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