Key Points

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.

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.