Esculetin ameliorates insulin resistance and type 2 diabetic nephropathy through reversal of histone H3 acetylation and H2A lysine 119 monoubiquitination

Insulin resistance (IR) and type 2 diabetic nephropathy (T2DN) are associated with elevated renal expression of monocyte chemo-attractant protein (MCP1) and transforming growth factor-β (TGF-β). Posttranslational histone modifications (PTHMs) play significant role in regulating the expression of such devastating gene expressions. Esculetin, a natural coumarin derivative possesses antioxidant, anti-proliferative and anti-inflammatory potential and has also been reported to revert PTHMs in IR and T2D heart. Thus, we hypothesized that esculetin treatment may show reno-protective effects in high fat diet fed (HFD) and HFD + low dose streptozotocin treated Wistar rats. Our results substantiate that esculetin bestows reno-protection owing to its renin angiotensin system modulating properties and also abrogating the hyper acetylation of histone H3 lysine (K) 14 and 18 and elevated H2AK119 monoubiquitination (Ub). This is the first report demonstrating that esculetin could be attributed to elevation of the occupancy of H2AK119Ub at the promoter regions of Mcp1 and Tgfb1.