WTAP regulates DDX3Y mRNA via m6A modification to promote high glucose-induced podocytes injury and diabetic nephropathy progression

Diabetic nephropathy (DN) is a major complication of diabetes, imposing substantial socioeconomic and public health challenges. N6-methyladenosine (m6A) modification, a prevalent epigenetic mechanism, influences cellular processes and disease progression. Wilms' tumor 1-associating protein (WTAP), an m6A methyltransferase subunit, was investigated for its role in DN. Bioinformatics identified differentially expressed genes in DN, and a high glucose (HG)-induced podocyte model was established to mimic DN in vitro. Techniques like Western blot, CCK-8, ELISA, flow cytometry, and TUNEL evaluated protein expression, cell viability, inflammation, oxidative stress, and apoptosis. SRAMP predicted m6A sites in DDX3Y mRNA, validated by MeRIP, while xenograft models confirmed in vivo effects. DDX3Y expression was elevated in DN and HG-induced podocytes, and sh-DDX3Y attenuated HG-induced injury. WTAP promoted DDX3Y mRNA stability via m6A methylation, exacerbating podocyte dysfunction. In diabetic mice, WTAP modulated DDX3Y to induce renal insufficiency and histopathological damage. Collectively, WTAP regulates DDX3Y via m6A methylation to promote HG-induced podocyte injury and DN progression.