4-Octyl itaconate protects against renal fibrosis via inhibiting TGF-β/Smad pathway, autophagy and reducing generation of reactive oxygen species

Renal fibrosis is an inevitable course of all kinds of progressive chronic kidney disease (CKD). Itaconic acid is an endogenous metabolite that has shown anti-inflammatory and antioxidant effects. 4-octyl itaconate (OI), a derivative of itaconic acid with higher fat solubility, can penetrate the cell membranes and be metabolized into itaconic acid in vitro. However, whether OI has an anti-renal fibrotic effect is still unclear. The current study purposed to investigate the anti-fibrotic effect in renal and the underlying mechanisms of OI. The unilateral ureteral occlusion (UUO) model and adenine-induced fibrosis model in Sprague-Dawley (SD) rats and Transforming growth factor-β1 (TGF-β1) induced HK-2 cells were applied to investigate the renoprotective effects of OI. This study reports for the first time that OI ameliorated renal fibrosis by suppressing the activation of TGF-β/Smad and nuclear factor kappa B (NF-κB) pathways, reducing generation of reactive oxygen species and inhibiting autophagy. These results clearly suggest that OI has great clinical potential for managing renal fibrosis.