Investigation of the variants at the binding site of inflammatory transcription factor NF-κB in patients with end-stage renal disease

Abstract

Background A chronic inflammatory state is a prominent feature in patients with end-stage renal disease (ESRD). Nuclear factor-kappa B (NF-κB) is a transcription factor that regulates the expression of genes involved in inflammation. Some genetic studies have demonstrated that the NF-κB genetic mutation could cause kidney injury and kidney disease progression. However, the association of a gene polymorphism in the transcription factor binding site of NF-κB with kidney disease is not clear. Methods We used the Taiwan Biobank database, the University of California, Santa Cruz, reference genome, and a chromatin immunoprecipitation sequencing database to find single nucleotide polymorphisms (SNPs) at potential binding sites of NF-κB. In addition, we performed a case–control study and genotyped 847 patients with ESRD and 846 healthy controls at Tri-Service General Hospital from 2015 to 2016. Furthermore, we used the ChIP assay to identify the binding activity of different genotypes and used Luciferase reporter assay to examine the function of the rs9395890 polymorphism. Result The results of biometric screening in the databases revealed 15 SNPs with the potential binding site of NF-κB. Genotype distributions of rs9395890 were significantly different in ESRD cases and healthy controls ( P = 0.049). The ChIP assay revealed an approximately 1.49-fold enrichment of NF-κB of the variant type TT when compared to that of the wild-type GG in rs9395890 ( P = 0.027; TT = 3.20 ± 0.16, GT = 2.81 ± 0.20, GG = 1.71 ± 0.18). The luciferase reporter assay showed that the NF-κB binding site activity in T allele was slightly higher than that in G allele, though it is not significant. Conclusions Our findings indicate that rs9395890 is associated with susceptibility to ESRD in Taiwan population. Electronic supplementary material The online version of this article (10.1186/s12882-019-1471-2) contains supplementary material, which is available to authorized users.

Promoter polymorphism of TNF‑α (rs1800629) is associated with ischemic stroke susceptibility in a southern Thai population

“…NF-κB acts as a critical transcription factor contributing to the transcription of various inflammatory genes, including IL-6 and TNF-α after cerebral ischemia-reperfusion injury ( 50 ). The DNA binding ability and transcriptional activity of NF-κB depend on the variants at the binding site of the NF-κB target gene, which modulate gene expression and influence disease risk ( 51 ). The molecular mechanism of how IL-6 and TNF-α gene polymorphisms influence the occurrence of IS remains to be elucidated.…”

MicroRNAs as Regulators of Immune and Inflammatory Responses: Potential Therapeutic Targets in Diabetic Nephropathy

“…Moreover, in a proximal-tubular epithelial cell DN model, decreased miR-141/200a promotes TGF-β2 mRNA translation and protein expression by diminishing miR-141/200a binding to the target site in the 3′-UTR (CAGUGUUA; http://www.targetscan.org ) of TGF-β2, resulting in increased expression of TGF-β2 (Wang et al, 2011 ). Excessive TGF-β largely accelerates IκBα mRNA decay to promote NF-κB/p50/p65 binding to IκBα, which enters the nucleus and induces gene transcription, which in turn induces inflammatory molecular changes (Yang et al, 2019 ). Then, activated NF-κB increases the accumulation of IL-1β, ICAM-1, and TNF-α and induces glomerular macrophage secretion and CD4 + Th17 T cell infiltration in glomerular and tubulointerstitial cells, eventually enhancing proximal tubule and tubulointerstitial inflammation and DN progression (Lan, 2011 ) ( Figure 8 ).…”

“…Then, the increased LMP7 promotes NF-κB activation (Sun et al, 2016 ). Moreover, signals include ligands binding to TNF receptor, T cell receptor, B cell receptor, and TLR–IL-1 receptors can activate a multisubunit IκB kinase complex to phosphorylate the IκB in renal cells (Yang et al, 2019 ). And then, the phosphorylated IκB comes through a proteasomal degradation, which will facilitate the nuclear translocation of free NF-κB, thus binding to the promoter and enhancer sites, and eventually initiating the transcription process.…”

Investigation of the relationship between sensorineural hearing loss and associated comorbidities in patients with chronic kidney disease: A nationwide, population-based cohort study

“…However, we were unable to compare the influence of oral and intravenous loop diuretic therapy since sequential intravenous-to-oral and oral-to-intravenous switch regimens were often used in clinical practice. Moreover, the other ototoxic drugs or genetic effects [58] that were not included may contribute bias. Finally, we did not investigate the underlying pathophysiological mechanism associating CKD with SNHL.…”