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Abstract
BackgroundHyperglycaemia in diabetes mellitus (DM) alters gene expression regulation in various organs and contributes to long term vascular and renal complications. We aimed to generate novel renal genome-wide gene transcription data in rat models of diabetes in order to test the responsiveness to hyperglycaemia and renal structural changes of positional candidate genes at selected diabetic nephropathy (DN) susceptibility loci.MethodsBoth Affymetrix and Illumina technologies were used to identify significant quantitative changes in the abundance of over 15,000 transcripts in kidney of models of spontaneous (genetically determined) mild hyperglycaemia and insulin resistance (Goto-Kakizaki-GK) and experimentally induced severe hyperglycaemia (Wistar-Kyoto-WKY rats injected with streptozotocin [STZ]).ResultsDifferent patterns of transcription regulation in the two rat models of diabetes likely underlie the roles of genetic variants and hyperglycaemia severity. The impact of prolonged hyperglycaemia on gene expression changes was more profound in STZ-WKY rats than in GK rats and involved largely different sets of genes. These included genes already tested in genetic studies of DN and a large number of protein coding sequences of unknown function which can be considered as functional and, when they map to DN loci, positional candidates for DN. Further expression analysis of rat orthologs of human DN positional candidate genes provided functional annotations of known and novel genes that are responsive to hyperglycaemia and may contribute to renal functional and/or structural alterations.ConclusionCombining transcriptomics in animal models and comparative genomics provides important information to improve functional annotations of disease susceptibility loci in humans and experimental support for testing candidate genes in human genetics.
Highlights
Hyperglycaemia in diabetes mellitus (DM) alters gene expression regulation in various organs and contributes to long term vascular and renal complications
We have investigated the effects of prolonged hyperglycaemia on genome-wide renal gene expression regulation in Goto Kakizaki (GK) rats and inbred rats of similar genetic origin (Wistar-Kyoto, WKY) made severely diabetic by STZ, which may be caused by differential adaptations to mild or severe hyperglycaemia induced by genetic variants in GK and environmental changes in both diabetic models
We demonstrated the possibility to use data from both comparative genomics and gene transcription regulation to test transcriptional responsiveness of genes to hyperglycaemia and renal structural changes that can improve functional annotations of known and potentially novel positional candidate genes localised in diabetic nephropathy (DN) susceptibility loci
Summary
Hyperglycaemia in diabetes mellitus (DM) alters gene expression regulation in various organs and contributes to long term vascular and renal complications. Genetic studies of nephropathy in diabetic patients are hampered by heterogeneous clinical features, including frequent association with hypertension, and betweenstudy variation in design and phenotype assessment [7]. High-throughput transcription profiling technologies, which are powerful tools for determining gene expression regulation in health and disease situations, can enrich genome annotations and uncover new DN candidates [14,15,16]. Such studies in patients and controls pose technical, scientific and ethical issues [17]
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