WTAP and METTL14 regulate the m6A modification of DKK3 in renal tubular epithelial cells of diabetic nephropathy.

Diabetic nephropathy (DN) is an important cause of death in diabetes patients, which is mainly due to its complex pathogenesis. Here, we explored the role of N6-methyladenosine (m6A) RNA methylation in DN development. Renal tubular epithelial cells from DN patients and experimental DN mice treated with streptozotocin (STZ) exhibited a considerable increase in METTL14 and WTAP expression as well as overall m6A methylation. Knocking down the expression of METTL14 and WTAP inhibited the migration and proliferation of tubular epithelial cells. MeRIP-seq analysis of the renal tissues of DN patients revealed that the genes with elevated m6A methylation were concentrated in the Wnt/β-Catenin signaling pathway. Dickkopf homolog 3 (DKK3) was screened out as the gene with the most significant increase in m6A methylation. In addition, the expression change pattern of DKK3 under DN circumstances is in line with those of METTL14 and WTAP. DKK3's m6A methylation sites were confirmed to be located in the 3′UTR region, which is how METTL14 and WTAP improved DKK3's mRNA stability. Finally, YTHDF1, a m6A reader, was demonstrated to recognize m6A-methylated DKK3 and promote DKK3 expression. • Total m6A level in the kidney is increased under diabetic nephropathy. • METTL14 and WTAP, act as m6A writer, are upregulated in tubular cells under DN. • m6A methylated DKK3 is upregulated under DN. • Urinary DKK3 is a biomarker of DN. • YTHDF1 is a reader protein of methylated DKK3 mRNA. [ABSTRACT FROM AUTHOR]