Involvement of c-Myc/WWP1/TRIM65 Axis in Renal Fibrosis

Area of Science:

• Molecular biology
• Renal pathophysiology
• Ubiquitin ligase function

Background:

• Maladaptive tubular repair significantly contributes to kidney fibrosis and chronic kidney disease (CKD).
• The precise molecular mechanisms governing this process are not fully understood.
• E3 ubiquitin ligases are critical in regulating cellular processes, including repair and fibrosis.

Purpose of the Study:

• To identify novel molecular regulators of maladaptive tubular repair and kidney fibrosis.
• To elucidate the signaling pathways involved in profibrotic factor-induced tubular damage.
• To evaluate the therapeutic potential of targeting identified regulators in CKD.

Main Methods:

• Investigated the role of E3 ubiquitin ligases WWP1 and TRIM65 in human and experimental CKD models.
• Utilized primary human renal epithelial cells and HK-2 cell lines to study PAI-1-induced fibrotic signaling.
• Employed gene silencing techniques (siRNA) to assess the impact of WWP1 and TRIM65.
• Analyzed signaling cascades involving PAI-1, c-Myc, BMP-7, and SMAD5 pathways.

Main Results:

• WWP1 and TRIM65 were significantly upregulated in both human and experimental CKD, with WWP1 levels correlating with reduced renal function.
• PAI-1 robustly induced WWP1 and TRIM65 expression in renal cells, promoting fibrotic signaling.
• Silencing WWP1 or TRIM65 attenuated PAI-1-induced fibrosis.
• A novel axis was identified: PAI-1 suppresses BMP-7/SMAD5, leading to c-Myc induction, which upregulates WWP1/TRIM65, promoting dedifferentiation and fibrosis.
• Restoring BMP-7 or SMAD5 signaling reduced fibrosis.

Conclusions:

• WWP1 and TRIM65 are novel, key regulators of tubular fibrosis in the context of maladaptive repair.
• The PAI-1-c-Myc-WWP1/TRIM65 signaling axis plays a critical role in driving kidney fibrosis.
• WWP1 represents a promising therapeutic target for mitigating CKD progression.