TET2 aggravates podocyte mitotic catastrophe and renal injury in diabetic nephropathy via m5C-dependent downregulation of Wee1 and activation of CDK1-cyclinB1 signaling.

Podocyte injury and loss in diabetic nephropathy (DN) are driven by mitotic catastrophe (MC), a disastrous cell death caused by aberrant cell cycle re-entry. Ten-eleven translocation 2 (TET2), a 5-methylcytosine (m5C) RNA demethylase, was upregulated in DN and regulated cell proliferation. Here, we explored whether TET2 mediates podocyte MC in DN using Adriamycin (ADM) and high glucose (HG) in vitro, and both STZ-induced and db/db diabetic mouse models in vivo. TET2 was upregulated in human diseased kidneys and injured podocytes, and its expression correlated with disease severity and podocyte loss. EdU staining and flow cytometry verified that ADM/HG facilitated cell proliferation and G2/M phase transition via elevated CDK1-cyclin B1 phosphorylation; meanwhile, ADM/HG increased reactive oxygen species and malondialdehyde levels. TET2 overexpression further enhanced ADM/HG-induced podocyte MC and oxidative stress, whereas TET2 knockdown had the opposite effect. Mechanistically, TET2 reduced Wee1 mRNA stability in an m5C-dependent manner, leading to CDK1-cyclin B1 activation. Rescue experiments confirmed that Wee1 reintroduction rescued TET2-driven MC and oxidative stress, while Wee1 silencing abolished the protection from TET2 knockdown. In vivo, TET2 depletion or Wee1 overexpression alleviated podocyte MC, renal injury, and apoptotic podocytes in both diabetic models. Collectively, TET2 promotes podocyte MC and aggravates DN via TET2-mediated m5C demethylation that suppresses Wee1 expression and activates CDK1-cyclin B1, suggesting that this axis may represent a candidate pathway in the context of DN.