Fibroblast growth factor 18 attenuates renal fibrosis via AMPK/NOX4 pathway in mice

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Tubulointerstitial fibrosis is a key driver of chronic kidney disease (CKD) progression.
• Fibroblast growth factors (FGFs) are implicated in kidney pathophysiology, but FGF18's specific role remains elusive.
• Understanding FGF18's function is crucial for developing novel therapeutic strategies for renal fibrosis.

Purpose of the Study:

• To investigate the role of FGF18 in the pathogenesis of renal fibrosis.
• To elucidate the underlying molecular mechanisms by which FGF18 influences kidney fibrosis.
• To assess the therapeutic potential of FGF18 in a preclinical model of renal fibrosis.

Main Methods:

• Induction of renal fibrosis using folic acid (FA) in a mouse model.
• Stimulation of human proximal tubular (HK-2) cells with transforming growth factor β (TGF-β).
• Overexpression of FGF18 in the kidney and assessment of fibrotic markers, oxidative stress, and signaling pathways (AMPK, NOX4).

Main Results:

• FGF18 expression was significantly upregulated in both FA-induced renal fibrosis and TGF-β-stimulated HK-2 cells.
• Overexpression of FGF18 ameliorated FA-induced renal fibrosis and reduced oxidative stress.
• FGF18 upregulated AMP-activated protein kinase (AMPK) phosphorylation via FGFR3, decreasing NOX4-ROS levels and inhibiting fibrosis-related protein expression.

Conclusions:

• FGF18 demonstrates a protective effect against folic acid-induced renal fibrosis.
• The mechanism involves FGF18 activating the AMPK/NOX4 pathway, leading to reduced oxidative stress and fibrosis.
• FGF18 represents a potential therapeutic target for mitigating renal fibrosis in chronic kidney disease.