Diabetes such as the TGF? pathway, which

Diabetes mellitus is a metabolic disorder characterized by high blood glucose levels over a prolonged period of time (WHO, 2014). This hyperglycaemic state can lead to numerous conditions, including diabetic nephropathy (DN), which affects approximately 40% of type 1 and type 2 diabetic patients (Gross et al., 2005). DN is defined as a loss of kidney function and is characterised by glomerular hyperfusion and hyperfiltratrion, leading to glomerular basement thickening, mesengial cell matrix overproduction, and tubulointerstitial fibrosis (Dronavalli et al., 2008). Progression of DN can be observed in several key stages that are associated with increased activation of certain pathways, such as the TGF? pathway, which is involved in renal fibrosis and is a main player in DN pathogenesis (Villeneuve and Natarajan, 2010).When discussing DN pathogenesis and progression, it is imperative to acknowledge the phenomenon known as metabolic memory, in which the negative effects of hyperglycaemia persist even after normal blood glucose levels have been restored (Tonna et al., 2010). Central to this concept is the role of epigenetic modifications specifically post translational histone modifications, with histone lysine methylation being shown to be implicated in metabolic memory (Villeneuve and Natarajan, 2010). Post translational histone modifications alter the affinity of histone tails to DNA, thus determining whether or not chromatin is condensed and therefore whether a gene is active or silenced. Hyperglycaemia, as observed in diabetes, leads to the activation of various DN associated pathways, which in turn can lead to increased production of certain growth factors, such as TGF?, and thus activation of specific transcription factors (Villeneuve and Natarajan, 2010). A gain in histone modification activating pathways, coupled with a loss in silencing histone modification pathways can then lead to epigenetic modifications that cause the prolonged expression of diabetes/DN associated genes, even after a normal glycaemic state is achieved (Villeneuve and Natarajan, 2010). Further understanding of the role of metabolic memory in diabetes and DN is therefore crucial for the development of therapeutic approaches to these diseases.TGF?, whilst being widely implicated in DN pathogenesis, is also involved in many other cellular processes such as differentiation and apoptosis (Mullen et al., 2011). The TGF? signalling pathway involves the activation of the TGF? superfamily ligand members which then bind to the TGF?-type II receptor, which subsequently recruits, phosphorylates and thus activates the TGF?-type I receptor (Verrecchia and Mauviel, 2002). Signalling between the TGF?-type I receptor and the nucleus occurs when the TGF?-type 1 receptor phosphorylates receptor-activated Smads (Smad2/3), which then form complexes with Co-Smad (Smad4), and are then transported to the nucleus where they may act as transcription factors and regulate target gene expression (Verrecchia and Mauviel, 2002).