WTAP-mediated N-methyladenosine Modification of NLRP3 MRNA in Kidney Injury of Diabetic Nephropathy

Overview

Journal Cell Mol Biol Lett

Publisher Biomed Central

Specialties Biochemistry
Cell Biology
Molecular Biology

Date 2022 Jun 27

PMID 35761192

Authors

Jianzi Lan

Bowen Xu

Xin Shi

Qi Pan

Qing Tao

Affiliations

Soon will be listed here.

Abstract

Background: Diabetic nephropathy (DN) is prevalent in patients with diabetes. N-methyladenosine (mA) 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 mA.

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 mA 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 mA 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 mA methylation of NLRP3 mRNA to upregulate NLRP3 inflammasome activation, which further induces cell pyroptosis and inflammation.

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