Yu Shanshan, Li Xiang, Wang Ting, Li Jingyi, Li Hongzhi, Xu Ying, Hu Yanling, Zhu Fubin, Wang Jinwei, Wang Tianhe, Zhu Bin, Zhou Xu-Jie, Zhang Hong, Lv Jicheng, Barratt Jonathan, Zhao Binghai
Nephrosis Precision Medicine Innovation Center, University of Beihua School of Medicine, Beihua University, Jilin, China.
Department of Nephrology, Zhejiang Provincial People's Hospital, the Affiliated People's Hospital, School of Basic Medicine, Hangzhou Medical College, Hangzhou, China.
J Am Soc Nephrol. 2024 Dec 1;35(12):1686-1701. doi: 10.1681/ASN.0000000000000441. Epub 2024 Aug 13.
Dysregulated IgA production plays a key role in the pathogenesis of IgA nephropathy. Increased 5-methylcytosine modification, an epigenetic regulatory mechanism, exaggerated IgA nephropathy phenotype in mice. Conversely, inhibition of 5-methylcytosine modification ameliorated progression of IgA nephropathy–like kidney disease in mice.
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.
To decipher the role of RNA 5mC in regulation of IgA class switch, the microRNA (miR)-23b and (Chinese Industrial Microbial Culture Collection Center) cell wall extract–induced Kawasaki disease mice were treated with 5-azacytidine. and double / mice and mice or / mice were also used.
We showed that downregulated expression of Transfer RNA Aspartic Acid Methyltransferase 1 and consequently reduced 5mC (mC) RNA modification and IgA synthesis in B cells. Inhibition of mC RNA modification normalized serum IgA levels and ameliorated progression of the IgA nephropathy–like kidney disease in and Kawasaki disease mice, while mesangial IgA and C3 deposition failed to develop in mice. By contrast, increased mC RNA modification resulted in an exaggerated IgA nephropathy phenotype. regulation of serum IgA levels and the development of an IgA nephropathy–like kidney disease in 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.
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.
IgA产生失调在IgA肾病的发病机制中起关键作用。5-甲基胞嘧啶修饰增加作为一种表观遗传调控机制，使小鼠IgA肾病表型加剧。相反，抑制5-甲基胞嘧啶修饰可改善小鼠IgA肾病样肾脏疾病的进展。
IgA肾病是全球肾衰竭的重要病因。IgA产生失调被认为在IgA肾病发病机制中起关键作用；然而，对于诸如RNA 5-甲基胞嘧啶（5mC）修饰等表观遗传机制在调节IgA合成中的作用知之甚少。
为了解RNA 5mC在调节IgA类别转换中的作用，用5-氮杂胞苷处理微小RNA（miR）-23b和（中国工业微生物菌种保藏管理中心）细胞壁提取物诱导的川崎病小鼠。还使用了双/小鼠和小鼠或/小鼠。
我们发现下调了天冬氨酸转运RNA甲基转移酶1的表达，从而降低了B细胞中的5mC（mC）RNA修饰和IgA合成。抑制mC RNA修饰可使血清IgA水平正常化，并改善和川崎病小鼠中IgA肾病样肾脏疾病的进展，而系膜IgA和C3沉积在小鼠中未发生。相比之下，mC RNA修饰增加导致IgA肾病表型加剧。和川崎病小鼠中血清IgA水平的调节以及IgA肾病样肾脏疾病的发生可能是通过B细胞中TRDMT1驱动的5mC RNA修饰介导的，导致活化诱导的胞苷脱氨酶活性受损和IgA类别转换重组。
本研究揭示了TRDMT1诱导的RNA 5mC甲基化调节IgA类别转换，并且5-氮杂胞苷抑制RNA 5mC可改善IgA肾病的进展。
