Epigenetics in Kidney Transplantation: Current Evidence, Predictions, and Future Research Directions

Abstract

Epigenetic modifications are changes to the genome that occur without any alteration in DNA sequence. These changes include cytosine methylation of DNA at cytosine-phosphate diester-guanine dinucleotides, histone modifications, microRNA interactions, and chromatin remodeling complexes. Epigenetic modifications may exert their effect independently or complementary to genetic variants and have the potential to modify gene expression. These modifications are dynamic, potentially heritable, and can be induced by environmental stimuli or drugs. There is emerging evidence that epigenetics play an important role in health and disease. However, the impact of epigenetic modifications on the outcomes of kidney transplantation is currently poorly understood and deserves further exploration. Kidney transplantation is the best treatment option for end-stage renal disease, but allograft loss remains a significant challenge that leads to increased morbidity and return to dialysis. Epigenetic modifications may influence the activation, proliferation, and differentiation of the immune cells, and therefore may have a critical role in the host immune response to the allograft and its outcome. The epigenome of the donor may also impact kidney graft survival, especially those epigenetic modifications associated with early transplant stressors (e.g., cold ischemia time) and donor aging. In the present review, we discuss evidence supporting the role of epigenetic modifications in ischemia-reperfusion injury, host immune response to the graft, and graft response to injury as potential new tools for the diagnosis and prediction of graft function, and new therapeutic targets for improving outcomes of kidney transplantation.

Figure 1:. Schema showing main components of epigenetic machinery and its role in regulation of gene expression

(1) DNA methylation: DNA methylation primarily involves the covalent binding of a methyl group to the cytosine pyrimidine ring in cytosine-phosphate diester-guanine (CpG) islands. CpG islands are high-density clusters of CpG dinucleotide; these are associated with gene promoters and are conserved across species. Methylation of the cytosine residues at CpG sites is catalyzed by DNA methyltransferases, which provide a unique epigenetic signature that regulates chromatin organization and gene expression. Methylation of cytosines in CpG dinucleotides is associated with inactive, condensed states of the chromosome. (2) Histone modifications: The core histones (H2A, H2B, H3 and H4), together with the 147 base pairs of genomic DNA wrapped around them, comprise the nucleosomes, which are the basic units of chromatin. The interactions between DNA and histones determine the degree of chromatin condensation and, consequently, of gene expression. (3) Small noncoding RNAs: Mature functional microRNAs of approximately 22 nucleotides are generated from long primary microRNA (pri-microRNA) transcripts. First, the pri-microRNAs, are processed in the nucleus into stem-loop precursors (pre-microRNA) of approximately 70 nucleotides by the RNase III endonuclease Drosha and its partner Pasha. The pre-microRNAs are then actively transported into the cytoplasm by exportin 5 and Ran-GTP and further processed into small RNA duplexes of approximately 22 nucleotides by the Dicer RNase III enzyme and its partner Loqacious (Loqs). The functional strand of the microRNA duplex is then loaded into the RNA-induced silencing complex (RISC). Finally, the microRNA guides the RISC to the cognate messenger RNA (mRNA) target for translational repression or degradation of mRNA.

Figure 2:. Effect of miRNAs in the regulation of mechanisms related to graft injury and reparation.

Epigenetic modifications, including altered patterns of miRNAs, affect the donor and recipient early in the kidney transplant process. I/R injury has been associated with differential expression of miRNAs. miR-21 is among the most highly up-regulated miRNA in acute kidney injury (–108). After KT, acute process such as ACR, ABMR, and CNIT also associate with specific miRNA profiles that regulate the expression of hundreds of genes from the immune system. These miRNAs affect both innate and adaptive immune response to graft (–140). The final outcome of the graft depends on the ability to repair and remodel. Persistent injury to the allograft leads to chronic inflammation and fibrogenesis, resulting in CRAD (with IF/TA) and loss of graft function. MiRNAs have been associated with fibrosis (–169). MiRNAs can influence tissue fibrogenesis through various mechanisms. miRNAs can be essential downstream components of both fibrogenic and fibrosis-suppressive signaling pathways, and changes in miRNA expression directly affect the biological response following activation of these pathways. Three TGF-β-regulated miRNA families, miR-21, miR-200, and miR-29 have been shown to modulate renal fibrosis. MiR-21, through a feed-forward loop, amplifies TGF-β signaling and promotes fibrosis. Conversely, miR-200 and miR-29 reduce fibrosis by inhibiting epithelial-to-mesenchymal transition and preventing the deposition of extracellular matrix, respectively (–175). Inhibition of miR-21 expression or augmenting miR-29 expression prevents kidney fibrosis in mice (170, 173).

Figure 3:. Epigenetics modifications in kidney transplantation.

The kidney transplant model is characterized by the combination of two genotypes (donor and recipient). Each genome is affected for epigenetic modifications associated with pre-transplant conditions (e.g., chronic illness, aging) and also peri-surgical factors (e.g., ischemia, ischemia reperfusion injury). Post-transplantation, the recipient immune system (also characterized by a unique epigenome) is responsible for the magnitude of the allo-response. On the other hand, the donor graft is responsible of the intensity of the response to the chronic injury with consequent inflammation, tissue reparation, and fibrogenesis that will conduct to nephron loss. The balance between these interactions will conduct to the overall graft and patient outcome. A better understanding of these epigenetic modifications in both, donors and recipients, may lead to identification of biomarkers of graft quality, improvement in transplant recipient selection, and progress in overall outcome prediction. Additionally, new therapeutic interventions can be expected (after refining drug specificity), as a result of the expanding research in epigenetics in kidney transplantation.