DKK3 promotes renal fibrosis by increasing MFF-mediated mitochondrial dysfunction in Wnt/β-catenin pathway-dependent...

Area of Science:

• Nephrology
• Molecular Biology
• Biochemistry

Background:

• Chronic kidney disease (CKD) is a progressive condition with limited therapeutic options.
• Renal fibrosis (RF) is a key pathological outcome of CKD, contributing to kidney dysfunction.
• The role of Dickkopf 3 (DKK3) in CKD pathogenesis, particularly its underlying mechanisms, remains incompletely understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which Dickkopf 3 (DKK3) contributes to renal fibrosis (RF) in chronic kidney disease (CKD).
• To investigate the regulatory pathway involving m6A modification, Wnt/β-catenin signaling, and MFF expression in DKK3-mediated RF.

Main Methods:

• Utilized hydrogen peroxide (H₂O₂)-treated HK-2 cells and unilateral ureteric obstruction (UUO) mouse models to simulate RF.
• Assessed kidney function, apoptosis, oxidative stress, and mitochondrial function using various biochemical and histological techniques.
• Employed molecular biology methods including Western blotting, qRT-PCR, immunofluorescence, and dual luciferase assays to determine molecular interactions and expression levels.

Main Results:

• DKK3 expression was significantly upregulated in both RF models.
• DKK3 knockdown ameliorated kidney damage, reduced oxidative stress, and inhibited apoptosis and mitochondrial dysfunction in UUO mice and HK-2 cells.
• Mechanistically, DKK3 upregulation was linked to METTL3-mediated m6A modification, which activated the TCF4/β-catenin pathway and increased MFF transcription.

Conclusions:

• DKK3, upregulated by m6A modification, promotes RF progression by activating the Wnt/β-catenin pathway and increasing MFF expression.
• This cascade leads to mitochondrial dysfunction and oxidative stress, highlighting DKK3 as a potential therapeutic target in CKD.