m5C demethylase TET2 promotes autophagy and alleviates podocyte injury in diabetic nephropathy by regulating RRAGC.

RNA modification is a widespread post-transcriptional regulatory process, of which 5-methylcytosine (m5C) is an important part of the RNA modification regulatory network. Ten-eleven translocation 2 (TET2), a demethylase of m5C, has been regarded as an important factor in a variety of diseases. However, the role of TET2 in diabetic nephropathy (DN) and its mechanism remain elusive. Here, we found that m5C modification was significantly increased in the kidney of diabetic mice, which was caused by decreased levels of TET2. Renal biopsy samples from patients diagnosed with type 2 DN, together with normal peritumoural tissues from renal carcinoma patients, were obtained and accompanied by corresponding clinical profiles. In the glomeruli of patients with DN, a pronounced downregulation of TET2 expression was observed. TET2 levels were significantly associated with podocyte markers and indicators of renal function, suggesting its potential relevance to DN progression. Functional studies revealed that overexpression of TET2 alleviated high glucose (HG)-induced podocyte damage by enhancing autophagy in both db/db mice models and cultured podocytes. Furthermore, the downstream molecular mechanisms were investigated by identifying m5C-methylated target transcripts Ras related GTP binding C (RRAGC) through m5C methylated RNA immunoprecipitation sequencing (MeRIP-seq). Mechanistically, TET2 attenuated HG-induced autophagy defects by decreasing the m5C level and mRNA stability of RRAGC, potentially involving the m5C reader Y-box binding protein 1 (YBX1). This work may open new avenues for exploring preventive and therapeutic strategies for DN.