LKB1 activated by NaB inhibits the IL-4/STAT6 axis and ameliorates renal fibrosis through the suppression of M2 macrophage polarization

Background

Renal fibrosis is a critical pathological characteristic of chronic kidney disease, and current antifibrotic therapies has limited efficacy. Sodium butyrate (NaB) has been shown to be highly effective in mitigating bleomycin-induced pulmonary fibrosis; however, its specific impact on renal fibrosis and the underlying mechanisms remain unclear. This study aims to elucidate the role and mechanism of NaB in renal fibrosis by using a mouse model of renal fibrosis induced through Unilateral Ureteral Obstruction (UUO) and folic acid (FA) administration.

Results

NaB significantly decreased the distribution of collagen fibers in renal tissues and mitigated fibrosis in a dose-dependent manner. Further analysis indicated that NaB inhibited M2 macrophage polarization in the renal tissues of UUO model mice by blocking the phosphorylation of STAT6, hence reducing renal fibrosis. Additionally, in vitro experiments demonstrated that NaB inhibited fibroblast activation induced by M2 macrophages. Mechanistic studies revealed that NaB attenuates fibroblast activation and M2 macrophage polarization by upregulating LKB1 and inhibiting the activation of the STAT6 signaling pathway.

Conclusion

NaB may exert its effects by inhibiting the activation of the IL-4/STAT6 signaling pathway through the upregulation of LKB1, which suppress the polarization of M2 macrophages and consequently reduce renal fibrosis. These findings establish a theoretical foundation for NaB as a novel drug candidate for renal fibrosis and indicate its potential applicability in clinical treatments for this condition.