Arid2-IR promotes NF-κB-mediated renal inflammation by targeting NLRC5 transcription

Cell Mol Life Sci. 2021 Mar;78(5):2387-2404. doi: 10.1007/s00018-020-03659-9. Epub 2020 Oct 22.

Abstract

Increasing evidence shows that long non-coding RNAs (lncRNAs) play an important role in a variety of disorders including kidney diseases. It is well recognized that inflammation is the initial step of kidney injury and is largely mediated by nuclear factor Kappa B (NF-κB) signaling. We had previously identified lncRNA-Arid2-IR is an inflammatory lncRNA associated with NF-κB-mediated renal injury. In this study, we examined the regulatory mechanism through which Arid2-IR activates NF-κB signaling. We found that Arid2-IR was differentially expressed in response to various kidney injuries and was induced by transforming growth factor beta 1(TGF-β1). Using RNA sequencing and luciferase assays, we found that Arid2-IR regulated the activity of NF-κB signal via NLRC5-dependent mechanism. Arid2-IR masked the promoter motifs of NLRC5 to inhibit its transcription. In addition, during inflammatory response, Filamin A (Flna) was increased and functioned to trap Arid2-IR in cytoplasm, thereby preventing its nuclear translocation and inhibition of NLRC5 transcription. Thus, lncRNA Arid2-IR mediates NF-κB-driven renal inflammation via a NLRC5-dependent mechanism and targeting Arid2-IR may be a novel therapeutic strategy for inflammatory diseases in general.

Keywords: Arid2-IR; Flna; Inflammation; NF-κB; NLRC5.

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Gene Expression Profiling / methods
  • Gene Expression Regulation / drug effects
  • HEK293 Cells
  • Humans
  • Inflammation / genetics*
  • Inflammation / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kidney / metabolism*
  • Kidney / pathology
  • Kidney Diseases / genetics
  • Kidney Diseases / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • RNA, Long Noncoding / genetics*
  • Transcription, Genetic*
  • Transforming Growth Factor beta1 / pharmacology

Substances

  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • NLRC5 protein, mouse
  • RNA, Long Noncoding
  • Transforming Growth Factor beta1