Recently, it has also been shown that only a minority of DAC-mediated demethylated promoters are associated with nucleosome remodelling. Chromatin remodelling is required for gene reactivation after DNA demethylation as induced by DAC treatment and the combination of DNMT and histone deacetylase inhibitors has been shown to induce re-expression of tumour suppressor genes in ovarian and colon cancer cell cultures. A phase I study of DAC in combination with suberoylanilide hydroamic acid in patients with a range of tumour types has been reported. We show here that CGI demethylation is not generally Afatinib sufficient to change gene expression. However, it may change the epigenetic niche providing a permissive environment for histone remodelling. In this study, we have established an in vitro model of the epigenetic modification following prolonged treatment of demethylating agents. Since the effect was maintained after the cessation of treatment, it may provide a useful tool for testing the effects of histone modifying agents in a reduced DNA methylation environment. The data-set provided with this work provides a rich resource for further analysis related to both DNA methylation in general, 
the effect of demethylating agents at pharmacological dosages and to the epigenetic changes that underlie myelodysplastic syndrome. We believe that the full value of this can only be realised in combination with clinical data and we present it here as to make it available for further analysis. Fibroblast growth factor 23 is a phosphaturic hormone produced in response to an increase in phosphorus load or high levels of calcitriol or parathyroid hormone. FGF23 acts by inducing renal phosphate excretion by kidney proximal tubular cells through reduction of the expression of type 2a and 2c sodium phosphate co-transporters. FGF23 also suppresses the production of vitamin D��s active form in the kidney by inhibiting the synthetic enzyme 1a-hydroxylase, thereby acting as counter-regulatory hormone for vitamin D. The reduction in circulating 1,25dihydroxyvitamin D levels by FGF23 contributes to cause negative phosphate balance through limiting phosphate absorption from the intestine. FGF23 exerts its intrarenal biological function by binding to cognate FGF receptors requiring the presence of Klotho, a transmembrane protein highly expressed in the kidney, as a co-receptor. The site of synthesis of FGF23 is primarily the bone tissue, more specifically osteocytes and osteoblasts, although FGF23 is also espressed by brain, thymus, liver, spleen and heart. Since the kidney is an important target of FGF23, and the circulating levels of FGF23 have been found to increase in association with disease progression and cardiovascular events in chronic kidney disease and diabetic nephropathy, we wondered whether the kidney could be a source of FGF23 during the development of renal disease. Few data are so far available showing that renal tissue expressed FGF23 at very low level, if any, in normal conditions and in uremic rats. We took advantage of the Zucker diabetic fatty rat model of human type 2 diabetic nephropathy characterized by obesity, hyperlipidemia, insulin resistance, progressive renal injury and cardiac abnormalities and evaluated the expression of FGF23 in the kidney during the course of the disease. We also investigated whether renoprotective effects of ACE inhibitor in this model were associated with modulation of renal FGF23 and Klotho expression. The present study shows that the kidney of ZDF rats, a model resembling human type 2 diabetic nephropathy, expressed FGF23 starting from the age of 4 months when rats have already Nutlin-3 significant levels of proteinuria and signs of renal injury. FGF23 mRNA expression further increased with time as diabetic disease progressed, reaching levels that were 3�C4 times higher than at 4 months. To our knowledge this is the first evidence of FGF23 production by the kidney during renal disease progression. Upregulation of FGF23 mRNA resulted in the expression of the corresponding protein localized at proximal and distal tubules in focal areas of the kidney. A previous study by Mirams et al that analyzed FGF23 mRNA expression in several human tissues showed that FGF23 was detectable in kidney tissue at low levels. Actually, the highest expression was found in bone followed by kidney medulla, liver, thyroid and kidney cortex. FGF23 bone expression was approximately 30 times higher than renal expression in normal conditions, but no data are available that compared tissues from patients with renal disease.