Cross-Communication Between Histone Acetyltransferase And Histone Deacetylase Epigenetic Enzymes Augments Oxidative Stress And Fibrosis In The Kidney Of Diabetic Mice

Background and Aims: Accumulating evidence implicates histone acetylation-based epigenetic mechanisms in the pathoetiology of diabetes-associated micro-/macrovascular complications. Diabetic nephropathy is a progressive chronic inflammatory microvascular disorder affecting the glomerular capillaries, a condition that ultimately impairs kidney function. Hitherto, the involvement of histone acetyltransferase (HAT) and histone deacetylase (HDAC) crosstalk in mediating diabetes-induced glomerular damage has not been explored. The aim of this study was to investigate the potential role of HAT and HDAC in the regulation of renal oxidative stress and fibrosis in diabetic mice. Methods: Non-diabetic and streptozotocin-induced diabetic C57BL/6J mice were randomized to receive vehicle, C646 (p300/HAT inhibitor) or SAHA (HDAC inhibitor) for 4 weeks. In vitro studies were performed on a human endothelial cell line. Masson's trichrome staining, immunofluorescence (IF) microscopy, in situ detection of reactive oxygen species (ROS), and luciferase gene reporter assays were employed. Results: Morphometric analysis revealed significant increases in glomerular volume in diabetic mice as compared to non-diabetic animals. IF microscopy assays demonstrated that increased abundance of NADPH oxidase subtypes, 4-hydroxynonenal-protein adducts, extracellular matrix proteins (fibronectin, collagen IV, laminin) correlated with ROS overproduction in the glomeruli of diabetic mice. Treatment of diabetic mice with C646/SAHA reduced glomerular volume and the levels of oxidative stress and markers of fibrosis. In vitro studies demonstrated that HAT and HDAC positively regulates the function of pro-inflammatory transcription factors. Conclusions: Our study provides evidence that pharmacological inhibition of HAT or HDAC isoforms may be important therapeutic strategies in diabetic kidney disease. Acknowledgements: Work supported by UEFISCDI (PN-III-P4-ID-PCE-2016-0665, PN-III-P1-1.1-TE-2016-0851, PN-III-P4-ID-PCCF-2016-0172).