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Differential Gene Expression in Diabetic Nephropathy in Individuals With Type 1 Diabetes
M Luiza Caramori1, Youngki Kim1, Allison B Goldfine1
1Departments of Medicine and Pediatrics (M.L.C., M.M.), and Pediatrics and Laboratory Medicine and Pathology (Y.K.), University of Minnesota, Minneapolis, Minnesota 55455; Joslin Diabetes Center (A.B.G., A.S.K.), Harvard Medical School, Boston, Massachusetts 02115; Department of Genetics (J.H.M.), Institute for Biomedical Informatics, Department of Biostatistics and Epidemiology, Perelman School of Medicine, Dartmouth College, Hanover, New Hampshire 03755; Departments of Public Health Sciences (S.S.R.), and Bioinformatics and Genetics (J.C.M.), University of Virginia, Charlottesville, Virginia 22908; Department of Genetics (D.K.), Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota 55455; and JDRF (H.N.), New York, New York 10004.
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.
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