Abstract
ABSTRACTTo define renal molecular mechanisms that are affected by permanent hyperglycaemia and might promote phenotypes relevant to diabetic nephropathy, we carried out linkage analysis of genome-wide gene transcription in the kidneys of F2 offspring from the Goto-Kakizaki (GK) rat model of type 2 diabetes and normoglycaemic Brown Norway (BN) rats. We mapped 2526 statistically significant expression quantitative trait loci (eQTLs) in the cross. More than 40% of eQTLs mapped in the close vicinity of the linked transcripts, underlying possible cis-regulatory mechanisms of gene expression. We identified eQTL hotspots on chromosomes 5 and 9 regulating the expression of 80-165 genes, sex or cross direction effects, and enriched metabolic and immunological processes by segregating GK alleles. Comparative analysis with adipose tissue eQTLs in the same cross showed that 496 eQTLs, in addition to the top enriched biological pathways, are conserved in the two tissues. Extensive similarities in eQTLs mapped in the GK rat and in the spontaneously hypertensive rat (SHR) suggest a common aetiology of disease phenotypes common to the two strains, including insulin resistance, which is a prominent pathophysiological feature in both GK rats and SHRs. Our data shed light on shared and tissue-specific molecular mechanisms that might underlie aetiological aspects of insulin resistance in the context of spontaneously occurring hyperglycaemia and hypertension.
Highlights
Transcriptome-based molecular phenotyping provides detailed information on the expression of individual genes and biological pathways
Genetic mapping of genome-wide gene transcription control in the diabetic kidney in (GK×Brown Norway (BN)) F2 rats We have previously shown that adult rats (7 months old) of our GK colony exhibit varying degrees of thickening of the glomerular basement membrane and mild mesangial extracellular matrix expansion when compared with normoglycaemic BN control animals (Wallis et al, 2008)
To characterize the architecture of renal gene transcription that might account for these renal structural changes and for proteinuria that segregates in a GK×BN F2 cross (Nobrega et al, 2009), we applied an eQTL strategy to map genetic loci linked to quantitative variations in the abundance of renal transcripts in the GK×BN F2 offspring previously used for analysis of diabetes QTLs (Gauguier et al, 1996)
Summary
Transcriptome-based molecular phenotyping provides detailed information on the expression of individual genes and biological pathways. Mapping of eQTLs in humans has progressed from whole blood and cell systems (Dixon et al, 2007; Fairfax et al, 2012; Grundberg et al, 2012) to multiple postmortem organs in control individuals (Battle et al, 2017), which were used to identify genes and biological pathways causing chronic diseases through computational integration with genome-wide association study (GWAS) data (Gamazon et al, 2018) This strategy does not account for expected organspecific variation in gene expression in disease conditions, which requires access to biopsies from the affected tissues that are often impossible to collect in large groups of phenotypically homogeneous patients and healthy control subjects. These limitations underline the importance of preclinical models of human chronic diseases to define tissue-specific genetic control of gene transcription accurately in standardized experimental conditions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
