Costunolide Inhibits Chronic Kidney Disease Development by Attenuating IKKβ/NF-κB Pathway

Area of Science:

• Nephrology
• Pharmacology
• Molecular Biology

Background:

• Chronic kidney disease (CKD) is a global health issue with high mortality.
• Costunolide (CTD), a bioactive substance, shows therapeutic potential for CKD.
• Understanding CTD's mechanisms in CKD is crucial for treatment development.

Purpose of the Study:

• To investigate the therapeutic effects of costunolide (CTD) on kidney injury.
• To elucidate the underlying molecular mechanisms of CTD in treating chronic kidney disease (CKD).
• To evaluate CTD's impact on renal fibrosis, inflammation, and ferroptosis.

Main Methods:

• Established unilateral ureteral obstruction (UUO) and mouse models of renal fibrosis.
• Administered varying concentrations of CTD to assess therapeutic efficacy.
• Analyzed renal morphology, fibrosis, inflammation, and ferroptosis markers via gene expression and RNA sequencing.
• Investigated the role of IKKβ through overexpression and inhibition studies in vitro and in vivo.

Main Results:

• CTD significantly reduced fibrosis, inflammation, and ferroptosis in UUO-induced renal fibrosis models.
• RNA sequencing identified IKKβ as a key regulator in renal injury, with elevated expression in fibrotic models.
• Downregulating IKKβ inhibited ferroptosis and inflammation; conversely, IKKβ overexpression worsened renal fibrosis.
• CTD alleviated renal fibrosis and inflammation by inhibiting IKKβ expression and the IKKβ/NF-κB pathway.

Conclusions:

• Costunolide (CTD) mitigates renal fibrosis, ferroptosis, and inflammation in chronic kidney disease (CKD).
• CTD exerts its effects by modulating the IKKβ/NF-κB pathway.
• Targeting IKKβ presents a significant therapeutic potential for managing CKD.