WT1 ameliorates podocyte injury via repression of EZH2/β-catenin pathway in diabetic nephropathy

Area of Science:

• Nephrology
• Epigenetics
• Molecular Biology

Background:

• Diabetic nephropathy (DN) involves podocyte injury, a process influenced by epigenetic factors.
• Wilm's tumor 1 (WT1) and β-catenin have opposing roles in podocyte biology.
• The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is implicated in cellular processes relevant to DN.

Purpose of the Study:

• To investigate whether EZH2 promotes WT1-induced podocyte injury through β-catenin activation.
• To elucidate the underlying molecular mechanisms of this interaction.
• To assess the therapeutic potential of targeting WT1 and EZH2 in DN.

Main Methods:

• Investigated the interaction between WT1 and EZH2 in podocyte injury models.
• Utilized molecular biology techniques to examine the role of EZH2 in β-catenin signaling.
• Analyzed the effect of EZH2 on secreted frizzled-related protein 1 (SFRP-1) expression and histone modifications.
• Evaluated WT1's impact on renal function and podocyte injury markers in diabetic rat models and human DN patients.

Main Results:

• WT1 antagonized EZH2, thereby ameliorating β-catenin-mediated podocyte injury, reducing mesenchymal transition, apoptosis, and oxidative stress.
• EZH2 mediated WT1-induced β-catenin inactivation by repressing SFRP-1, a Wnt antagonist.
• EZH2-induced silencing of SFRP-1 was linked to increased H3K27me3 on its promoter.
• WT1 administration improved renal function, decreased podocyte injury, lowered serum creatinine, reduced proteinuria, and increased eGFR in diabetic rats and DN patients.

Conclusions:

• An epigenetic pathway involving the WT1/EZH2/β-catenin axis attenuates podocyte injury in DN.
• WT1 demonstrates clinical relevance by improving kidney function markers in DN.
• Targeting WT1 and EZH2 represents a potential therapeutic strategy for managing diabetic nephropathy.