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

Abstract

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.