WTAP-mediated N6-methyladenosine modification of NLRP3 mRNA in kidney injury of diabetic nephropathy

Cell Mol Biol Lett. 2022 Jun 27;27(1):51. doi: 10.1186/s11658-022-00350-8.


Background: Diabetic nephropathy (DN) is prevalent in patients with diabetes. N6-methyladenosine (m6A) methylation has been found to cause modification of nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing (NLRP) 3, which is involved in cell pyroptosis and inflammation. WTAP is a key gene in modulating NLRP3 m6A.

Methods: In this study, WTAP was silenced or overexpressed in high glucose (HG)-treated HK-2 cells to determine its influence on pyroptosis, NLRP3 inflammasome-related proteins, and the release of pro-inflammatory cytokines. NLRP3 expression and m6A levels were assessed in the presence of WTAP shRNA (shWTAP). WTAP expression in HK-2 cells was examined with the introduction of C646, a histone acetyltransferase p300 inhibitor.

Results: We found that WTAP expression was enhanced in patients with DN and in HG-treated HK-2 cells. Knockdown of WTAP attenuated HG-induced cell pyroptosis and NLRP3-related pro-inflammatory cytokines in both HK-2 cells and db/db mice, whereas WTAP overexpression promoted these cellular processes in HK-2 cells. WTAP mediated the m6A of NLRP3 mRNA that was stabilized by insulin-like growth factor 2 mRNA binding protein 1. Histone acetyltransferase p300 regulated WTAP expression. WTAP mRNA levels were positively correlated with NLRP3 inflammasome components and pro-inflammatory cytokines.

Conclusion: Taken together, WTAP promotes the m6A methylation of NLRP3 mRNA to upregulate NLRP3 inflammasome activation, which further induces cell pyroptosis and inflammation.

Keywords: High glucose; Inflammation; N 6-methyladenosine; NLRP3; Pyroptosis; WTAP.

MeSH terms

  • Adenosine / analogs & derivatives
  • Animals
  • Cell Cycle Proteins
  • Cytokines / metabolism
  • Diabetes Mellitus*
  • Diabetic Nephropathies* / genetics
  • Diabetic Nephropathies* / metabolism
  • Histone Acetyltransferases / metabolism
  • Humans
  • Inflammasomes / metabolism
  • Inflammation
  • Kidney / metabolism
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • RNA Splicing Factors
  • RNA, Messenger / genetics


  • Cell Cycle Proteins
  • Cytokines
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • RNA Splicing Factors
  • RNA, Messenger
  • WTAP protein, human
  • N-methyladenosine
  • Histone Acetyltransferases
  • Adenosine