Department of Surgery, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan.
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Phytomedicine. 2020 Dec;79:153352. doi: 10.1016/j.phymed.2020.153352. Epub 2020 Sep 21.
Withaferin A is a functional ingredient of a traditional medicinal plant, Withania somnifera, which has been broadly used in India for protecting against chronic diseases. This bioactive steroidal lactone possesses multiple functions such as anti-oxidation, anti-inflammation, and immunomodulation. Chronic kidney disease (CKD) is one of the major health problems worldwide with the high complication, morbidity, and mortality rates. The detailed effects and underlying mechanisms of withaferin A on CKD progression still remain to be clarified.
We aimed to investigate whether withaferin A treatment ameliorates the development of renal fibrosis and its related mechanisms in a CKD mouse model.
A mouse model of unilateral ureteral obstruction (UUO) was used to mimic the progression of CKD. Male adult C57BL/6J mice were orally administered with 3 mg/kg/day withaferin A for 14 consecutive days after UUO surgery. Candesartan (5 mg/kg/day) was used as a positive control.
Both Withaferin A and candesartan treatments significantly ameliorated the histopathological changes and collagen deposition in the UUO kidneys. Withaferin A could significantly reverse the increases in the protein levels of pro-fibrotic factors (fibronectin, transforming growth factor-β, and α-smooth muscle actin), inflammatory signaling molecules (phosphorylated nuclear factor-κB-p65, interleukin-1β, and cyclooxygenase-2), and cleaved caspase-3, apoptosis, and infiltration of neutrophils in the UUO kidneys. The protein levels of endoplasmic reticulum (ER) stress-associated molecules (GRP78, GRP94, ATF4, CHOP, phosphorylated eIF2α, and cleaved caspase 12) were increased in the kidneys of UUO mice, which could be significantly reversed by withaferin A treatment.
Withaferin A protects against the CKD progression that is, at least in part, associated with the moderation of ER stress-related apoptosis, inflammation, and fibrosis in the kidneys of CKD. Withaferin A may serve as a potential therapeutic agent for the development of CKD.
铁皮石斛素 A 是一种传统药用植物铁皮石斛的功能性成分，在印度被广泛用于预防慢性疾病。这种生物活性甾体内酯具有多种功能，如抗氧化、抗炎和免疫调节。慢性肾脏病 (CKD) 是全球主要的健康问题之一，其并发症、发病率和死亡率都很高。铁皮石斛素 A 对 CKD 进展的具体影响和潜在机制仍有待阐明。
我们旨在研究铁皮石斛素 A 是否能改善 CKD 小鼠模型的肾纤维化发展及其相关机制。
采用单侧输尿管梗阻 (UUO) 小鼠模型模拟 CKD 的进展。雄性成年 C57BL/6J 小鼠在 UUO 手术后连续 14 天每天口服 3mg/kg 铁皮石斛素 A。坎地沙坦（5mg/kg/天）作为阳性对照。
铁皮石斛素 A 和坎地沙坦治疗均显著改善了 UUO 肾脏的组织病理学变化和胶原沉积。铁皮石斛素 A 可显著逆转 UUO 肾脏中促纤维化因子（纤连蛋白、转化生长因子-β和α-平滑肌肌动蛋白）、炎症信号分子（磷酸化核因子-κB-p65、白细胞介素-1β和环氧化酶-2）和裂解的 caspase-3、凋亡和中性粒细胞浸润的增加。内质网 (ER) 应激相关分子（GRP78、GRP94、ATF4、CHOP、磷酸化 eIF2α 和裂解的 caspase12）的蛋白水平在 UUO 小鼠肾脏中升高，铁皮石斛素 A 治疗可显著逆转这一现象。
铁皮石斛素 A 可预防 CKD 进展，至少部分原因是减轻了 CKD 肾脏中与 ER 应激相关的细胞凋亡、炎症和纤维化。铁皮石斛素 A 可能成为治疗 CKD 的潜在药物。
