Epigenetics refers to heritable changes in gene expression patterns not caused by an altered nucleotide sequence, and includes non-coding RNAs and covalent modifications of DNA and histones. This review focuses on functional evidence for the involvement of DNA and histone epigenetic modifications in the pathogenesis of kidney disease and the potential therapeutic implications. There is evidence of activation of epigenetic regulatory mechanisms in acute kidney injury (AKI), chronic kidney disease (CKD) and the AKI-to-CKD transition of diverse aetiologies, including ischaemia-reperfusion injury, nephrotoxicity, ureteral obstruction, diabetes, glomerulonephritis and polycystic kidney disease. A beneficial in vivo effect over preclinical kidney injury has been reported for drugs that decrease DNA methylation by either inhibiting DNA methylation (e.g. 5-azacytidine and decitabine) or activating DNA demethylation (e.g. hydralazine), decrease histone methylation by inhibiting histone methyltransferases, increase histone acetylation by inhibiting histone deacetylases (HDACs, e.g. valproic acid, vorinostat, entinostat), increase histone crotonylation (crotonate) or interfere with histone modification readers [e.g. inhibits of bromodomain and extra-terminal proteins (BET)]. Most preclinical studies addressed CKD or the AKI-to-CKD transition. Crotonate administration protected from nephrotoxic AKI, but evidence is conflicting on DNA methylation inhibitors for preclinical AKI. Several drugs targeting epigenetic regulators are in clinical development or use, most of them for malignancy. The BET inhibitor apabetalone is in Phase 3 trials for atherosclerosis, kidney function being a secondary endpoint, but nephrotoxicity was reported for DNA and HDAC inhibitors. While research into epigenetic modulators may provide novel therapies for kidney disease, caution should be exercised based on the clinical nephrotoxicity of some drugs.

In conclusion, albumin directly decreases Klotho expression in cultured tubular cells. This may explain, or at least contribute to, the decrease in Klotho and promote fibroblast growth factor 23 resistance in early CKD categories, as observed in preclinical and clinical proteinuric kidney disease.

An improved understanding of pathogenic pathways in AKI may identify novel therapeutic approaches. Previously, we conducted unbiased liquid chromatography-tandem mass spectrometry-based protein expression profiling of the renal proteome in mice with acute folate nephropathy. Here, analysis of the dataset identified enrichment of pathways involving NFB in the kidney cortex, and a targeted data mining approach identified components of the noncanonical NFB pathway, including the upstream kinase mitogen-activated protein kinase kinase kinase 14 (MAP3K14), the NFB DNA binding heterodimer RelB/NFB2, and proteins involved in NFB2 p100 ubiquitination and proteasomal processing to p52, as upregulated. Immunohistochemistry localized MAP3K14 expression to tubular cells in acute folate nephropathy and human AKI. , kidney expression levels of NFB2 p100 and p52 increased rapidly after folic acid injection, as did DNA binding of RelB and NFB2, detected in nuclei isolated from the kidneys. Compared with wild-type mice, MAP3K14 activity-deficient aly/aly (MAP3K14) mice had less kidney dysfunction, inflammation, and apoptosis in acute folate nephropathy and less kidney dysfunction and a lower mortality rate in cisplatin-induced AKI. The exchange of bone marrow between wild-type and MAP3K14 mice did not affect the survival rate of either group after folic acid injection. In cultured tubular cells, MAP3K14 small interfering RNA targeting decreased inflammation and cell death. Additionally, cell culture and studies identified the chemokines MCP-1, RANTES, and CXCL10 as MAP3K14 targets in tubular cells. In conclusion, MAP3K14 promotes kidney injury through promotion of inflammation and cell death and is a promising novel therapeutic target.