B-Cell Epigenetic Modulation of IgA Response by 5-Azacytidine and IgA Nephropathy,Journal of the American Society of Nephrology

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B-Cell Epigenetic Modulation of IgA Response by 5-Azacytidine and IgA Nephropathy
Journal of the American Society of Nephrology ( IF 10.3 ) Pub Date : 2024-08-13 , DOI: 10.1681/asn.0000000000000441
Shanshan Yu _{1,

2} , Xiang Li _{1,

2} , Ting Wang ₁ , Jingyi Li ₃ , Hongzhi Li ₁ , Ying Xu ₄ , Yanling Hu ₅ , Fubin Zhu ₂ , Jinwei Wang ₃ , Tianhe Wang ₂ , Bin Zhu ₂ , Xu-Jie Zhou ₃ , Hong Zhang ₃ , Jicheng Lv ₃ , Jonathan Barratt ₆ , Binghai Zhao _{1,

2}

Affiliation

ion of IgA nephropathy–like kidney disease in mice. Background IgA nephropathy is an important global cause of kidney failure. Dysregulation of IgA production is believed to play a key role in IgA nephropathy pathogenesis; however, little is known about the epigenetic mechanisms, such as RNA 5-methylcytosine (5mC) modification, in regulating IgA synthesis. Methods To decipher the role of RNA 5mC in regulation of IgA class switch, the microRNA (miR)-23b−/− and Lactobacillus casei (Chinese Industrial Microbial Culture Collection Center) cell wall extract–induced Kawasaki disease mice were treated with 5-azacytidine. Trdmt1−/− and double Trdmt1−/−/miR-23b−/− mice and Aid−/− mice or Aid−/−/miR-23b−/− mice were also used. Results We showed that miR-23b downregulated expression of Transfer RNA Aspartic Acid Methyltransferase 1 and consequently reduced 5mC (m5C) RNA modification and IgA synthesis in B cells. Inhibition of m5C RNA modification normalized serum IgA levels and ameliorated progression of the IgA nephropathy–like kidney disease in miR-23b−/− and Kawasaki disease mice, while mesangial IgA and C3 deposition failed to develop in Trdmt1−/−miR-23b−/− mice. By contrast, increased m5C RNA modification resulted in an exaggerated IgA nephropathy phenotype. miR-23b regulation of serum IgA levels and the development of an IgA nephropathy–like kidney disease in miR-23b−/− and Kawasaki disease mice is likely mediated through TRDMT1-driven 5mC RNA modification in B cells, resulting in impaired activation-induced cytidine deaminase activity and IgA class switch recombination. Conclusions This study revealed TRDMT1-induced RNA 5mC methylation regulated IgA class switch, and inhibition of RNA 5mC by 5-azacytidine ameliorated progression of IgA nephropathy....

更新日期：2024-08-13

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