P0976ALTERED EXPRESSION OF LONG NON-CODING AND MESSENGER RNAS IN DIABETIC NEPHROPATHY FOLLOWING TREATMENT WITH ROSIGLITAZONE

Abstract

Abstract Background and Aims The value of rosiglitazone (RSG) in the protection of kidneys from diabetic injury was recognized, however, the adverse systemic side effects limit its clinical application. Long noncoding RNAs (lncRNAs) are primarily described as signal molecules since they interact with cellular components, and have been shown to exhibit strong tissue and cell specificity. The aim of this study is to elucidate the novel renoprotective molecular mechanism of RSG and to propose lncRNA targets for diabetic nephropathy treatment, which may provide a new approach to avoid systemic side effects of RSG. Method Db/db mice were treated with RSG as dbR group or vehicle as dbdb group, and db/m mice as control group. Plasma, urine and kidney cortex were collected, and unbiased RNA sequencing of three renal cortical samples from each group was performed. Results Db/db mice developed hyperglycemia, impaired intra-peritoneal glucose tolerance, proteinuria, decreased mitochondrial SOD activity, podocyte impairment, epithelial-mesenchymal transition, glomerulosclerosis and tubulointerstitial fibrosis, however, RSG treatment improved these changes. RNA-seq profiling revealed that the development of DN caused an up-regulation in the expression of 1176 mRNAs and a down-regulation in the expression of 1010 mRNAs (p<0.05) compared to controls, with the expression of 251 mRNAs being returned to normal following treatment with RSG. Further, 88 up-regulated and 68 down-regulated lncRNAs (p<0.05) were identified in db/db mice compared to controls, 10 of which had their normal expression restored following treatment with RSG. Bioinformatic analysis revealed that the primary pathways involved in the pathogenesis of DN, and subsequently in the therapeutic effects of PPARγ, are related to inflammatory and metabolic processes. Six lncRNAs that exhibited opposite expression patterns in dbdb vs. control and dbR vs. dbdb analyses were randomly chosen and qualified by qRT-PCR, including a novel lncRNA and lncRNA-AI838599. From GSEA analysis, three co-expressed mRNAs of lncRNA-AI838599 (Gadd45b, Per1 and Sphk1) were cores enriched in the Hallmark TNFα signaling via NFκb Gene Set (MSigDB). Conclusion RSG treatment can attenuate DN in experimental models through regulation of metabolism and inflammation, and lncRNA-AI838599 emerges as a key rosiglitazone-regulated gene in DN treatment through TNFα-NFκb pathway.