Abstract
Diabetic nephropathy (DN) as the primary cause of end-stage kidney disease is a common complication of diabetes. Recent researches have shown the activation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome are associated with inflammation in the progression of DN, but the exact mechanism is unclear. Long noncoding RNAs (lncRNAs) have roles in the development of many diseases including DN. However, the relationship between lncRNAs and inflammation in DN remains largely unknown. Our previous study has revealed that 14 lncRNAs are abnormally expressed in DN by RNA sequencing and real-time quantitative PCR (qRT-PCR) in the renal tissues of db/db DN mice. In this study, these lncRNAs were verified their expressions by qRT-PCR in mesangial cells (MCs) cultured under high- and low-glucose conditions. Twelve lncRNAs displayed the same expressional tendencies in both renal tissues and MCs. In particular, long intergenic noncoding RNA (lincRNA)-Gm4419 was the only one associating with NF-κB among these 12 lncRNAs by bioinformatics methods. Moreover, Gm4419 knockdown could obviously inhibit the expressions of pro-inflammatory cytokines and renal fibrosis biomarkers, and reduce cell proliferation in MCs under high-glucose condition, whereas overexpression of Gm4419 could increase the inflammation, fibrosis and cell proliferation in MCs under low-glucose condition. Interestingly, our results showed that Gm4419 could activate the NF-κB pathway by directly interacting with p50, the subunit of NF-κB. In addition, we found that p50 could interact with NLRP3 inflammasome in MCs. In conclusion, our findings suggest lincRNA-Gm4419 may participate in the inflammation, fibrosis and proliferation in MCs under high-glucose condition through NF-κB/NLRP3 inflammasome signaling pathway, and may provide new insights into the regulation of Gm4419 during the progression of DN.
Highlights
Diabetic nephropathy (DN) as the primary cause of end-stage kidney disease is a common complication of diabetes mellitus.[1]
By qRT-PCR and Fluorescence in situ hybridization (FISH), we found that p50 (+) resulted in increased the total, cytoplasmic and nuclear expression of Gm4419 compared with the L-mesangial cells (MCs) mock and L-MC pcDNA3.1 (Figures 4a–c)
Studies have reported long noncoding RNA (lncRNA) participated in the DN
Summary
Diabetic nephropathy (DN) as the primary cause of end-stage kidney disease is a common complication of diabetes mellitus.[1]. Recent studies utilizing high-throughput RNA sequencing (RNA-seq) technology and chromatin immunoprecipitation (ChIP) sequencing technology have identified thousands of abnormally expressed lncRNAs.[24] By using RNA-Seq and real-time quantitative PCR (qRT-PCR), we recently identified 14 dysexpession lncRNAs in the kidney tissues of db/db DN mice including lncRNA-Gm4419. It indicates that Gm4419 may be involved in DN. Our data display that Gm4419 may have important roles in inflammation, fibrosis and cell proliferation in DN via NF-κB/NLRP3 inflammasome signaling pathway
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