Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease
Open Access
- 9 June 2020
- journal article
- review article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 21 (11), 4113
- https://doi.org/10.3390/ijms21114113
Abstract
Diabetic kidney disease is one of the fastest growing causes of death worldwide. Epigenetic regulators control gene expression and are potential therapeutic targets. There is functional interventional evidence for a role of DNA methylation and the histone post-translational modifications—histone methylation, acetylation and crotonylation—in the pathogenesis of kidney disease, including diabetic kidney disease. Readers of epigenetic marks, such as bromodomain and extra terminal (BET) proteins, are also therapeutic targets. Thus, the BD2 selective BET inhibitor apabetalone was the first epigenetic regulator to undergo phase-3 clinical trials in diabetic kidney disease with an endpoint of kidney function. The direct therapeutic modulation of epigenetic features is possible through pharmacological modulators of the specific enzymes involved and through the therapeutic use of the required substrates. Of further interest is the characterization of potential indirect effects of nephroprotective drugs on epigenetic regulation. Thus, SGLT2 inhibitors increase the circulating and tissue levels of β-hydroxybutyrate, a molecule that generates a specific histone modification, β-hydroxybutyrylation, which has been associated with the beneficial health effects of fasting. To what extent this impact on epigenetic regulation may underlie or contribute to the so-far unclear molecular mechanisms of cardio- and nephroprotection offered by SGLT2 inhibitors merits further in-depth studies.Funding Information
- Instituto de Salud Carlos III (PI15/00298, CP14/00133, PI16/01900, PI18/01386, PI18/0133, PI19/00588, PI19/00815, DTS18/00032, ERA-PerMed-JTC2018 (KIDNEY ATTACK AC18/00064 and PERSTIGAN AC18/00071), ISCIII-RETIC REDinREN RD016/0009),)
This publication has 167 references indexed in Scilit:
- p300 Is Elevated in Systemic Sclerosis and Its Expression Is Positively Regulated by TGF-β: Epigenetic Feed-Forward Amplification of FibrosisJournal of Investigative Dermatology, 2013
- Beyond proteinuria: VDR activation reduces renal inflammation in experimental diabetic nephropathyAmerican Journal of Physiology-Renal Physiology, 2012
- Identification of 67 Histone Marks and Histone Lysine Crotonylation as a New Type of Histone ModificationCell, 2011
- Genomic mapping of 5-hydroxymethylcytosine in the human brainNucleic Acids Research, 2011
- Brd4 Coactivates Transcriptional Activation of NF-κB via Specific Binding to Acetylated RelAMolecular and Cellular Biology, 2009
- Role of the Histone H3 Lysine 4 Methyltransferase, SET7/9, in the Regulation of NF-κB-dependent Inflammatory GenesOnline Journal of Public Health Informatics, 2008
- Change in post‐translational modifications of histone H3, heat‐shock protein‐27 and MAP kinase p38 expression by curcumin in streptozotocin‐induced type I diabetic nephropathyBritish Journal of Pharmacology, 2008
- Differential Regulation of NF-κB by Elongation Factors Is Determined by Core Promoter TypeMolecular and Cellular Biology, 2007
- Chromatin Modifications and Their FunctionCell, 2007
- Histone Demethylation Mediated by the Nuclear Amine Oxidase Homolog LSD1Cell, 2004