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Epigenetic regulation in AKI and kidney repair: mechanisms and therapeutic implications

Abstract

Acute kidney injury (AKI) is a major public health concern associated with high morbidity and mortality. Despite decades of research, the pathogenesis of AKI remains incompletely understood and effective therapies are lacking. An increasing body of evidence suggests a role for epigenetic regulation in the process of AKI and kidney repair, involving remarkable changes in histone modifications, DNA methylation and the expression of various non-coding RNAs. For instance, increases in levels of histone acetylation seem to protect kidneys from AKI and promote kidney repair. AKI is also associated with changes in genome-wide and gene-specific DNA methylation; however, the role and regulation of DNA methylation in kidney injury and repair remains largely elusive. MicroRNAs have been studied quite extensively in AKI, and a plethora of specific microRNAs have been implicated in the pathogenesis of AKI. Emerging research suggests potential for microRNAs as novel diagnostic biomarkers of AKI. Further investigation into these epigenetic mechanisms will not only generate novel insights into the mechanisms of AKI and kidney repair but also might lead to new strategies for the diagnosis and therapy of this disease.

Key points

  • Acute kidney injury (AKI) and subsequent kidney repair are associated with substantial epigenetic changes that have important roles in the pathogenesis and outcome of AKI.

  • An overall increase in histone acetylation (for example, with the use of histone deacetylase inhibitors) might attenuate AKI and promote kidney repair, but the enzymes and downstream genes that mediate these effects remain elusive.

  • DNA methylation might also affect AKI and kidney repair via modulation of downstream genes, but the nature of this regulation remains largely unknown.

  • MicroRNAs are important factors in the regulation of AKI and kidney repair, but they can be pathogenic or protective depending on the specific microRNA species.

  • Additional research into the epigenetic mechanisms underlying AKI may lead to the discovery of novel biomarkers and therapies for AKI.

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Related links

Long Noncoding RNA Database v2.0: http://www.lncrnadb.org

miRBase 22: http://www.miRbase.org

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Acknowledgements

The authors are supported in part by grants from the US National Institutes of Health (DK058831 and DK087843) and the US Department of Veterans Affairs (BX000319). Z.D. is a recipient of the Senior Research Career Scientist award from the Department of Veterans Affairs.

Reviewer information

Nature Reviews Nephrology thanks J. Lorenzen, A. B. Sanz, T. Tanaka and S. Zhuang for their contribution to the peer review of this work.

Author information

C.G. and Z.D. researched data for the article and wrote the article. All authors contributed substantially to discussion of the article’s content and reviewed and edited the article before submission.

Competing interests

The authors declare no competing interests.

Correspondence to Zheng Dong.

Glossary

Epigenetic writers

Specific enzymes that add epigenetic marks on histone proteins or DNA.

Epigenetic readers

Effector proteins that recognize and bind epigenetic marks.

Epigenetic erasers

Specific enzymes that remove the epigenetic marks on histone proteins or DNA.

Core histones

Histones H2A, H2B, H3 and H4, which form the nucleosome core (also known as the histone octamer).

Linker histones

Histones that bind to internucleosomal DNA (also known as linker DNA), facilitating the formation of a compact chromatin structure.

Histone acetylation

Histone modification that involves the addition of an acetyl group to the ε-amine of lysine on all four core histones by histone acetyltransferases.

Histone methylation

Histone modification that involves the addition of a methyl group to a basic amino acid on core histones by histone methyltransferases.

Histone crotonylation

Histone modification that adds a crotonyl group to lysine residues on the core histones by histone crotonyltransferases.

Matrix chromatin immunoprecipitation

High-throughput chromatin immunoprecipitation method in which antibodies are immobilized in a 96-well plate and all the procedures are done on the same plate without sample transfer.

Permissive histone marks

Histone modifications that promote gene transcription.

Elongation marks

Histone modifications that promote transcription elongation.

Repressive histone marks

Histone modifications that inhibit gene transcription.

CpG dinucleotides

Regions of DNA in which a cytosine nucleotide is followed by a guanine nucleotide, connected by a phosphodiester bond.

CpG islands

Regions of DNA >200 base pairs in length that have a CG content >50% and observed CpG (number of CpGs observed in a window):expected CpG (number of Cs × number of Gs/window length) ratio ≥0.6.

Genomic integrity

Integrity of the genome or genome stability.

X chromosome inactivation

Process that inactivates one of the two X chromosomes in female mammals.

Genomic imprinting

Biological process that epigenetically marks a gene, leading to gene expression in a parent-of-origin manner.

Hemimethylated DNA

DNA that has one strand methylated and another unmethylated.

tRNAs

Class of small RNA that carries a particular amino acid to the ribosome on the basis of the mRNA nucleotide sequences.

DNA hydroxymethylome profiling

Genome-wide analysis of DNA hydroxymethylation.

Hyper-hydroxymethylation

Increased DNA hydroxymethylation.

Reduced representation bisulfite sequencing

(RRBS). Genome-wide DNA methylation analysis method based on bisulfite sequencing that involves sequencing of a reduced, representative sample of the whole genome.

Small interfering RNAs

Class of small non-coding RNAs that bind to complementary mRNAs, leading to mRNA degradation and inhibition of protein translation.

Circulating non-coding RNAs

Non-coding RNAs that are present in the body fluid.

Dicer

Double-stranded RNA endoribonuclease that cleaves long or hairpin double-stranded RNA into small interfering RNA or precursor microRNA into microRNA.

Chromatin immunoprecipitation (ChIP) sequencing

Method combining chromatin immunoprecipitation and next-generation sequencing that analyses the genome-wide DNA binding sites for transcription factors or other chromatin-associated proteins.

Inspiratory hypoxia

Hypoxia condition that animals are subjected to with a low inspiratory oxygen concentration (such as 8% of oxygen).

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Further reading

Fig. 1: Pathophysiology of AKI and repair.
Fig. 2: Mechanisms and consequences of histone modifications.
Fig. 3: Mechanisms of DNA methylation and demethylation.
Fig. 4: Mechanisms of gene regulation by non-coding RNAs.