Differential gene expression in diabetic nephropathy in individuals with type 1 diabetes

Context: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) in the United States. Objective: The aim of this study was to determine whether there were skin fibroblast gene expression differences between subjects with type 1 diabetes (T1D) with or without DN. Setting: This was a cross-sectional study conducted in the University of Minnesota. Patients: Study volunteers were 100 former participants of Genetics of Kidneys in Diabetes: 40 were diabetic nephropathy (DN) Controls, normoalbuminuric after ≥ 15 years of T1D; and 60 were DN Cases, 25 with proteinuria and 35 with ESRD. Intervention(s): Skin fibroblasts were grown in high glucose (HG) for five passages (approximately 6 weeks). Main Outcome Measure(s): SF gene expression was assessed by transcriptome sequencing using the Illumina HiSeq 2000 platform. Pathway analyses tested directionally consistent group differences within the Kyoto Encyclopedia of Genes and Genomes pathways. Results: Eight pathways, all related to cell cycle and repair, were up-regulated in the DN Controls vs the DN Cases. These pathways markedly overlapped with the pathways up-regulated by HG in T1D monozygotic twins (MZT), but not in their non-T1D MZT. DN Cases showed statistical trends toward up-regulation of these pathways vs non-T1D MZT, but much less so than the DN Controls. Conclusions: Together, these data suggest that SF from T1D patients undergo epigenetic modifications resulting in increased expression of genes in healing and repair pathways. These responses, much more robust in patients protected from DN, suggest that epigenetic factors are important in DN risk.