Roxadustat ameliorates renal interstitial fibrosis through regulating the CX43/ZO-1 signaling pathway

Area of Science:

• Nephrology
• Pharmacology
• Molecular Biology

Background:

• Chronic kidney disease (CKD) is a prevalent condition with renal interstitial fibrosis (RIF) as a common outcome.
• The exact causes of RIF remain unclear, necessitating further research into therapeutic interventions.
• Roxadustat (FG4592), a hypoxia-inducible factor prolyl-hydroxylase inhibitor (HIF-PHI), shows potential in managing CKD-related anemia, but its mechanisms in mitigating kidney damage require elucidation.

Purpose of the Study:

• To investigate the protective effects of FG4592 pretreatment against the development of renal fibrosis.
• To elucidate the underlying mechanisms by which FG4592 may prevent or reverse RIF.
• To evaluate the therapeutic potential of FG4592 in models of kidney dysfunction and fibrosis.

Main Methods:

• Bioinformatics analysis was employed to propose a mechanism of action for FG4592.
• In vitro studies utilized human kidney-2 (HK-2) cells exposed to transforming growth factor-β (TGF-β) to assess FG4592's protective effects.
• Folic acid (FA) induced renal dysfunction models were used to evaluate FG4592's efficacy in vivo.

Main Results:

• FG4592 pretreatment was found to stabilize Hif-1α expression.
• FG4592 promoted the expression of tight junction proteins (connexin43 [CX43], zonula occludens-1 [ZO-1]) and adhesion molecule E-cadherin.
• FG4592 pretreatment improved TGF-β induced HK-2 cell damage and ameliorated FA-induced renal dysfunction, reducing inflammatory cytokines and restoring renal function.

Conclusions:

• FG4592 demonstrates a shielding influence against folic acid-induced renal dysfunction.
• FG4592 activates the Gap Junction signaling pathway, involving CX43 and ZO-1, to enhance tubular epithelial cell repair.
• FG4592 presents a promising therapeutic strategy for slowing the progression of renal fibrosis in CKD.