TET2 Deficiency Exacerbates Podocyte Injury and Mitophagy Disorder in Diabetic Nephropathy by Regulating M5C Methylation of Bcas3

Recent evidence highlights the critical role of 5‐methylcytidine (m5C) as an epigenetic modification in the pathogenesis of various diseases. However, its regulatory mechanisms in diabetic nephropathy (DN) remain poorly understood. In this study, we observed a marked increase in m5C levels in the kidneys of type 2 diabetic (db/db) mice and in high glucose (HG)‐stimulated podocytes, which was linked to reduced expression of the m5C demethylase ten‐eleven translocation 2 (TET2). Moreover, renal biopsy samples from patients with DN exhibited decreased TET2 expression, correlating with impaired renal function. Gain‐of‐function assays revealed that TET2 overexpression in HG‐induced podocytes enhanced mitophagy and ameliorated podocyte injury both in vitro and in vivo. Therapeutically, systemic delivery of AAV‐TET2 in db/db mice reduced albuminuria, improved renal histopathology, and restored mitophagy. Mechanistically, TET2 regulated mitophagy by modulating the m5C methylation of Breast Carcinoma Amplified Sequence 3 (Bcas3). Furthermore, Bcas3 overexpression promoted mitophagy and attenuated podocyte damage under HG conditions. In conclusion, TET2‐mediated m5C modification contributes to podocyte injury in DN, and targeting m5C via TET2 presents a promising therapeutic strategy for DN.