Details

Autor(en) / Beteiligte

• Fontecha-Barriuso, Miguel
• Martin-Sanchez, Diego
• Ruiz-Andres, Olga
• Poveda, Jonay
• Sanchez-Niño, Maria Dolores
• Valiño-Rivas, Lara
• Ruiz-Ortega, Marta
• Ortiz, Alberto
• Sanz, Ana Belén

Titel

Targeting epigenetic DNA and histone modifications to treat kidney disease

Ist Teil von

• Nephrology, dialysis, transplantation, 2018-11, Vol.33 (11), p.1875-1886

Ort / Verlag

England

Erscheinungsjahr

2018

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• 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.