a Department of Urology, The Central Hospital of Wuhan, Tongji Medical College , Huazhong University of Science and Technology , Wuhan , China.
b Department of Hand Surgery , Affiliated Nanhua Hospital of University of South China , Hengyang , China.
Pharm Biol. 2019 Dec;57(1):169-175. doi: 10.1080/13880209.2019.1577464.
Ursolic acid (UA; 3β-hydroxy-urs-12-en-28-oic acid), one of the pentacyclic triterpenoids found in various plants and herbs, possesses some beneficial effects under pathological conditions, including combating hepatic fibrosis.
This study investigates the effects of UA on renal tubulointerstitial fibrosis in vivo and in vitro.
In vivo, 24 male C57BL6 mice were divided into four groups. Eighteen mice were subjected to unilateral ureteral obstruction (UUO) and the remaining six sham-operated mice served as control. UUO mice received either vehicle or UA (50 or 100 mg/kg) by gastric gavage for 6 days. In vitro, HK-2 cells were treated with 10 or 50 μM UA and 10 ng/mL recombinant human transforming growth factor-β1 (TGF-β1). The molecular mechanisms of fibrosis were investigated.
UUO induced marked interstitial collagen I and fibronectin deposition and epithelial-mesenchymal transition (EMT), as evidenced by increased α-smooth muscle actin (α-SMA) and decreased E-cadherin. However, UA treatment significantly reduced collagen I and fibronectin accumulation in the fibrotic kidney. UA treatment also decreased α-SMA and preserved E-cadherin in vivo. In vitro, TGF-β1-treated HK-2 cells demonstrated elevated α-SMA, snail1, slug, TGF-β1, and p-smad3, as well as diminished E-cadherin. UA pretreatment prevented E-cadherin loss and diminished α-SMA expression in HK-2 cells. UA downregulated mRNA expression of snail1 and slug. UA also lowered TGF-β1 protein expression and p-Smad3 in HK-2 cells.
UA attenuated renal tubulointerstitial fibrosis by inhibiting EMT, and such inhibition may be achieved by decreasing profibrotic factors. UA may be a novel therapeutic agent for renal fibrosis.
乌苏酸（UA；3β-羟基-熊-12-烯-28-酸）是一种存在于各种植物和草药中的五环三萜，在病理条件下具有一些有益作用，包括对抗肝纤维化。
本研究探讨 UA 对体内和体外肾小管间质纤维化的影响。
体内实验中，将 24 只雄性 C57BL6 小鼠分为四组。18 只小鼠接受单侧输尿管梗阻（UUO），其余 6 只假手术小鼠作为对照。UUO 小鼠给予载体或 UA（50 或 100mg/kg）灌胃 6 天。体外实验中，用 10 或 50μM UA 和 10ng/mL 重组人转化生长因子-β1（TGF-β1）处理 HK-2 细胞。研究纤维化的分子机制。
UUO 诱导间质胶原 I 和纤维连接蛋白沉积和上皮间质转化（EMT），表现为α-平滑肌肌动蛋白（α-SMA）增加和 E-钙黏蛋白减少。然而，UA 治疗可显著减少纤维化肾脏中的胶原 I 和纤维连接蛋白积累。UA 治疗还可降低体内α-SMA 和保留 E-钙黏蛋白。体外，TGF-β1 处理的 HK-2 细胞表现出α-SMA、snail1、slug、TGF-β1 和 p-smad3 升高，以及 E-钙黏蛋白减少。UA 预处理可防止 HK-2 细胞中 E-钙黏蛋白丢失和减少α-SMA 表达。UA 下调 snail1 和 slug 的 mRNA 表达。UA 还降低了 HK-2 细胞中 TGF-β1 蛋白表达和 p-Smad3。
UA 通过抑制 EMT 减轻肾小管间质纤维化，这种抑制可能是通过降低促纤维化因子实现的。UA 可能是治疗肾纤维化的一种新型治疗剂。
