Methyltransferase-like 16 drives diabetic nephropathy progression via epigenetic suppression of V-set pre-B cell surrogate light chain 3.

AIMS

This study aims to elucidate how Methyltransferase-like 16 (METTL16), as a key m6A methyltransferase, contributes to the pathogenesis of diabetic nephropathy by regulating oxidative stress and gene expression through epigenetic mRNA methylation.

MATERIALS AND METHODS

In the present study, in vivo and in vitro DN models were established to investigate the role of METTL16 in disease progression. RNA-seq and m6A-seq were employed to identify downstream targets of METTL16 and validate its regulatory mechanisms. Intervention experiments were conducted to further elucidate the impact of this axis on DN progression.

KEY FINDINGS

In DN models, METTL16 expression was significantly upregulated, accompanied by an increase in m6A modification levels and enhanced YTH N6-methyladenosine RNA binding protein 2 (YTHDF2)-mediated recognition activity. Transcriptomic analysis identified v-set pre-B cell surrogate light chain (Vpreb3) as a downstream target of METTL16. In the DN model, Vpreb3 expression was suppressed through METTL16-mediated m6A modification and YTHDF2-mediated m6A-dependent mRNA degradation. Silencing METTL16 restored Vpreb3 expression and alleviated oxidative stress-induced kidney injury. The results of the present study indicated that METTL16 epigenetically suppresses Vpreb3 expression, exacerbating the progression of DN.

SIGNIFICANCE

This suggests that targeting this pathway could serve as a potential therapeutic strategy to mitigate oxidative stress and alleviate DN-associated renal injury.