State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
Eur J Pharmacol. 2020 Apr 15;873:172989. doi: 10.1016/j.ejphar.2020.172989. Epub 2020 Feb 4.
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.
肾纤维化是各种进行性慢性肾脏病（CKD）不可避免的发展过程。衣康酸是一种内源性代谢物，具有抗炎和抗氧化作用。4-辛基衣康酸（OI）是衣康酸的衍生物，脂溶性更高，能够穿透细胞膜，并在体外代谢为衣康酸。然而，OI 是否具有抗肾纤维化作用尚不清楚。本研究旨在探讨 OI 的抗肾纤维化作用及其潜在机制。采用单侧输尿管结扎（UUO）模型和腺嘌呤诱导的 Sprague-Dawley（SD）大鼠肾纤维化模型以及转化生长因子-β1（TGF-β1）诱导的人肾近端小管上皮细胞（HK-2）系，研究 OI 的肾保护作用。本研究首次报道，OI 通过抑制 TGF-β/Smad 和核因子 kappa B（NF-κB）通路的激活，减少活性氧的产生和抑制自噬，改善了肾纤维化。这些结果清楚地表明，OI 具有很大的临床潜力，可用于治疗肾纤维化。
