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RNA-seq analysis of the hypothalamic transcriptome reveals the networks regulating physiopathological progress in the diabetic GK rat.

ABSTRACT: The Goto-Kakizaki (GK) rat is an animal model of non-obese type 2 diabetes (T2D). The GK rat was generated through the introduction of various genetic mutations from continuous inbreeding; these rats develop diabetes spontaneously. The mutated genes in GK rats may play key roles in the regulation of diabetes. The hypothalamus plays a central role in systematic energy homeostasis. Here, the hypothalamic transcriptomes in GK and Wistar rats at 4, 8 and 12 weeks were investigated by RNA-seq, and multiple variants and gene expression profiles were obtained. The number of variants identified from GK rats was significantly greater than that of Wistar rats, indicating that many variants were fixed and heritable in GK rats after selective inbreeding. The differential gene expression analysis indicated that GK rats had a dysfunctional hypothalamic melanocortin system and attenuation of the hypothalamic glucose-sensing pathway. In addition, we generated integrated gene network modules by combining the protein-protein interaction (PPI) network, co-expression network and mutations in GK and Wistar rats. In the modules, GK-specific genes, such as Bad, Map2k2, Adcy3, Adcy2 and Gstm6, may play key roles in hypothalamic regulation in GK rats. Our research provides a comprehensive map of the abnormalities in the GK rat hypothalamus, which reveals the new mechanisms of pathogenesis of T2D.

SUBMITTER: Meng Y

PROVIDER: S-EPMC5039700 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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RNA-seq analysis of the hypothalamic transcriptome reveals the networks regulating physiopathological progress in the diabetic GK rat.

Meng Yuhuan Y Guan Yujia Y Zhang Wenlu W Wu Yu-E YE Jia Huanhuan H Zhang Yu Y Zhang Xiuqing X Du Hongli H Wang Xiaoning X

Scientific reports 20160928

The Goto-Kakizaki (GK) rat is an animal model of non-obese type 2 diabetes (T2D). The GK rat was generated through the introduction of various genetic mutations from continuous inbreeding; these rats develop diabetes spontaneously. The mutated genes in GK rats may play key roles in the regulation of diabetes. The hypothalamus plays a central role in systematic energy homeostasis. Here, the hypothalamic transcriptomes in GK and Wistar rats at 4, 8 and 12 weeks were investigated by RNA-seq, and mu ...[more]

PMID: 27677945

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Project description:UNLABELLED:The UT-A1 urea transporter is crucial to the kidney's ability to generate concentrated urine. Native UT-A1 from kidney inner medulla (IM) is a heavily glycosylated protein with two glycosylation forms of 97 and 117 kDa. In diabetes, UT-A1 protein abundance, particularly the 117 kD isoform, is significantly increased corresponding to an increased urea permeability in perfused IM collecting ducts, which plays an important role in preventing the osmotic diuresis caused by glucosuria. However, how the glycan carbohydrate structure change and the glycan related enzymes regulate kidney urea transport activity, particularly under diabetic condition, is largely unknown. In this study, using sugar-specific binding lectins, we found that the carbohydrate structure of UT-A1 is changed with increased amounts of sialic acid, fucose, and increased glycan branching under diabetic conditions. These changes were accompanied by altered UT-A1 association with the galectin proteins, ?-galactoside glycan binding proteins. To explore the molecular basis of the alterations of glycan structures, the highly sensitive next generation sequencing (NGS) technology, Illumina RNA-seq, was employed to analyze genes involved in the process of UT-A1 glycosylation using streptozotocin (STZ)-induced diabetic rat kidney. Differential gene expression analysis combining with quantitative PCR revealed that expression of a number of important glycosylation related genes were changed under diabetic conditions. These genes include the glycosyltransferase genes Mgat4a, the sialylation enzymes St3gal1 and St3gal4 and glycan binding protein galectin-3, -5, -8, and -9. In contrast, although highly expressed in kidney IM, the glycosyltransferase genes Mgat1, Mgat2, and fucosyltransferase Fut8, did not show any changes. CONCLUSIONS:In diabetes, not only is UT-A1 protein abundance increased but the protein's glycan structure is also significantly changed. UT-A1 protein becomes highly sialylated, fucosylated and branched. Consistently, a number of crucial glycosylation related genes are changed under diabetic conditions. The alteration of these genes may contribute to changes in the UT-A1 glycan structure and therefore modulate kidney urea transport activity and alleviate osmotic diuresis caused by glucosuria in diabetes.

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RNA-seq analysis of the hypothalamic transcriptome reveals the networks regulating physiopathological progress in the diabetic GK rat.

Publications

RNA-seq analysis of the hypothalamic transcriptome reveals the networks regulating physiopathological progress in the diabetic GK rat.

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