Kannan Harithpriya, Udyama Juttada, Ravichandran Jayasuriya, Satyavani Kumpatla, Vijay Viswanathan, Kunka Mohanram Ramkumar
Keywords
Nrf2 • HDACs • Microalbuminuria • Macroalbuminuria • Epigenetic regulation
Background Nuclear factor erythroid-2-related factor 2 (Nrf2) is a crucial transcription factor in maintaining cellular homeostasis. The regulation of Nrf2 expression is an essential target for treating diabetic nephropathy (DN), and this regulation has been reported to be influenced by epigenetics. Few studies highlighted that Nrf2 regulation is associated with epigenetic markers such as histone deacetylases (HDAC) and DNA methyltransferase (DNMTs).
Objective This cross-sectional study aimed to investigate the association of all isoform-specific HDACs and their correlation with Nrf2 expression with the development of DN among south Indian people with type 2 diabetes (T2DM).
Methods A case–control cross-sectional study was performed using 108 T2DM individuals, comprising 23 participants with only T2DM and 60 participants with DN without any other complications, and 25 healthy volunteers. The gene expression of Nrf2, its downstream targets, and all HDAC targets involved in this study were assessed using qPCR.
Results We observed a significant decrease in the gene expression of Nrf2 in the DN group compared to healthy controls. In parallel, a significant downregulation of HDAC3/7/8/9/10/11 and SIRT1/2/3/4/7 has been observed in DN subjects compared to T2DM. On the other hand, HDAC1/2/4/5/6 showed a significant upregulation in DN groups compared to T2DM. A significant negative correlation between Nrf2 and HDAC1/2/4/5 was observed, which infers an imbalance in the Nrf2-HDAC axis.
Discussion In summary, our study findings provide compelling evidence of the association between HDACs and Nrf2 in the pathogenesis of DN, shedding light on potential therapeutic avenues for this condition
