Abstract
Epigenetic changes might provide the biological explanation for the long-lasting impact of metabolic alterations of diabetic kidney disease development. Here we examined cytosine methylation of human kidney tubules using Illumina Infinium 450 K arrays from 91 subjects with and without diabetes and varying degrees of kidney disease using a cross-sectional design. We identify cytosine methylation changes associated with kidney structural damage and build a model for kidney function decline. We find that the methylation levels of 65 probes are associated with the degree of kidney fibrosis at genome wide significance. In total 471 probes improve the model for kidney function decline. Methylation probes associated with kidney damage and functional decline enrich on kidney regulatory regions and associate with gene expression changes, including epidermal growth factor (EGF). Altogether, our work shows that kidney methylation differences can be detected in patients with diabetic kidney disease and improve kidney function decline models indicating that they are potentially functionally important.
Highlights
Epigenetic changes might provide the biological explanation for the long-lasting impact of metabolic alterations of diabetic kidney disease development
Methylation probes associate with degree of interstitial fibrosis
Histopathological analyses and quantitative scoring of tubulointerstitial fibrosis were performed by a renal pathologist
Summary
Epigenetic changes might provide the biological explanation for the long-lasting impact of metabolic alterations of diabetic kidney disease development. 7 Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, School of Medicine, University of Pennsylvania Perelman, Philadelphia 19104 PA, USA. While there is increased risk of kidney disease development in patients with poor glycemic control, recent large interventional studies failed to show survival or renal benefit following normalization of blood glucose levels in patients with established diabetes[10,11,12]. These observations suggest that mechanisms outside of “traditional” genetic variants might be responsible for disease development. Metabolically driven epigenetic changes in the kidney could potentially explain the clinical observational data such as metabolic memory and developmental programming
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