TET2 Deficiency Exacerbates Podocyte Injury and Mitophagy Disorder in Diabetic Nephropathy by Regulating M5C...

Area of Science:

• Epigenetics
• Molecular Biology
• Nephrology

Background:

• 5-methylcytidine (m5C) is an epigenetic modification implicated in disease pathogenesis.
• The role and regulatory mechanisms of m5C in diabetic nephropathy (DN) are not well understood.

Purpose of the Study:

• To investigate the role of m5C and its regulatory enzyme, ten-eleven translocation 2 (TET2), in diabetic nephropathy (DN).
• To explore the therapeutic potential of targeting TET2 in DN.

Main Methods:

• Assessed m5C levels and TET2 expression in kidneys of type 2 diabetic mice (db/db) and high glucose (HG)-stimulated podocytes.
• Analyzed renal biopsy samples from DN patients.
• Performed gain-of-function assays for TET2 and Breast Carcinoma Amplified Sequence 3 (Bcas3) in vitro and in vivo.
• Utilized adeno-associated virus (AAV) mediated systemic delivery of TET2 in db/db mice.

Main Results:

• m5C levels were elevated, and TET2 expression was reduced in DN kidneys and podocytes, correlating with impaired renal function.
• TET2 overexpression ameliorated podocyte injury by enhancing mitophagy.
• AAV-TET2 delivery in db/db mice reduced albuminuria, improved renal histopathology, and restored mitophagy.
• TET2 regulated mitophagy via m5C modification of Bcas3, and Bcas3 overexpression also promoted mitophagy and attenuated podocyte damage.

Conclusions:

• TET2-mediated m5C modification plays a crucial role in podocyte injury in DN.
• Targeting m5C through TET2 represents a promising therapeutic strategy for DN.