WTAP-induced m⁶A Methylation of Atoh8 Promotes Cell Proliferation and Fibrosis in Diabetic Nephropathy

Diabetic nephropathy (DN) is a common diabetic complication, which increases morbidity of end-stage renal failure. N6-methyladenosine (m6A) modification has been reported in association with multiple physiological processes, however, its role in diabetic nephropathy is still poorly understood. Here, we found that the levels of m6A modification were up-regulated in both high-glucose-cultured mouse mesangial cells and the renal tissues from db/db mice. The key methyltransferase WT1 associated protein (WTAP) was primarily responsible for the elevated m6A modification. Moreover, WTAP knockdown significantly inhibited the proliferation and fibrosis of mouse mesangial cells (MMCs). Mechanistically, using the combination analysis of MeRIP-Seq and RNA-Seq, we revealed that Atoh8 was a downstream target of WTAP-induced m6A modification. We first revealed that Atoh8 was lowly expressed in renal tissues of DN model mice and HG-induced mesangial cells. WTAP reduced Atoh8 expression by inhibiting Atoh8 mRNA stability. Overexpression of Atoh8 restrained the proliferation and fibrosis of mesangial cells. This study provides novel insights into the role of m6A modification in DN and suggests that WTAP and Atoh8 could serve as potential therapeutic targets for this condition.