A Natural Small Molecule Mitigates Kidney Fibrosis by Targeting Cdc42-mediated GSK-3β/β-catenin Signaling

Area of Science:

• Pharmacology and Natural Products Chemistry
• Nephrology and Molecular Medicine

Background:

• Kidney fibrosis is a major cause of chronic kidney disease (CKD) progression and renal dysfunction.
• Current treatments for kidney fibrosis are limited, necessitating the search for novel therapeutic agents.
• Wikstroemia chamaedaphne is a medicinal plant with potential therapeutic properties.

Purpose of the Study:

• To identify and characterize novel anti-renal fibrotic compounds from Wikstroemia chamaedaphne.
• To elucidate the molecular mechanism of action of the identified compound.
• To evaluate the therapeutic potential of the compound in preclinical models of kidney fibrosis.

Main Methods:

• Bioassay-guided fractionation of Wikstroemia chamaedaphne extract to isolate active compounds.
• In vitro assays using cultured renal fibroblasts and in vivo studies in unilateral ureteral obstructed (UUO) mice.
• Thermal proteome profiling to identify the direct molecular target of the active compound.
• Western blotting and other molecular techniques to investigate downstream signaling pathways.

Main Results:

• Daphnepedunin A (DA), a daphne diterpenoid, was isolated and identified as a potent anti-kidney fibrosis agent.
• DA demonstrated superior efficacy compared to pirfenidone in reducing kidney fibrosis in vitro and in vivo.
• Cell division cycle 42 (Cdc42) was identified as the direct target of DA.
• DA inhibits Cdc42 activity, leading to the downregulation of downstream signaling pathways (p-PKCζ/p-GSK-3β) and blocking pro-fibrotic β-catenin signaling.

Conclusions:

• Cdc42 is a critical therapeutic target for mitigating kidney fibrosis.
• Daphnepedunin A (DA) is a potent inhibitor of Cdc42 and a promising lead compound for developing new treatments for chronic kidney diseases (CKDs).
• DA's mechanism involves blocking the classical pro-fibrotic β-catenin signaling pathway.