Chen Jing-Hsien, Wu Pei-Tzu, Chyau Charng-Cherng, Wu Pei-Hsuan, Lin Hui-Hsuan
Department of Nutrition, Chung Shan Medical University, Taichung City 40201, Taiwan.
Clinical Laboratory, Chung Shan Medical University Hospital, Taichung City 40201, Taiwan.
J Agric Food Chem. 2023 Jan 11;71(1):382-397. doi: 10.1021/acs.jafc.2c05720. Epub 2022 Dec 23.
Hyperuricemic nephropathy (HN) is caused by urate crystals that get deposited in the kidney and contribute to renal fibrosis. Uric acid (UA) has been proven to directly cause renal mesangial cell oxidative stress and fibrosis in the pathogenesis of HN. Some antioxidants can be used as chemopreventive agents of HN. leaf extracts (HLE), rich in polyphenol, have been shown to possess hypoglycemic, antioxidant, hypolipidemic, antiatherosclerotic, and anticancer effects. The aim of the study is to examine the inhibitory effect of HLE and its main component ellagic acid (EA) on renal fibrosis. , mouse renal glomerular mesangial SV40MES13 cells pretreated with UA were demonstrated to trigger obvious morphological changes and viability loss, as well as affect matrix metalloproteinases (MMPs) activities. Noncytotoxic doses of HLE and EA abolished the UA-induced cell injury and MMP-2/9 secretion. In addition, HLE and EA exhibited antioxidant and anti-inflammatory effects on the UA-treated cells with a reduction in transforming growth factor-beta (TGF-β) production. Next, the UA-activated pro-fibrotic factors, extracellular matrix (ECM) deposition, and epithelial-mesenchymal-transition (EMT) were inhibited by HLE or EA. Mechanistic assays indicated that antifibrotic effects of HLE might be mediated via TGF-β/Smad signaling, as confirmed by the transfection of Smad7 siRNA. , HLE and EA supplementations significantly alleviated HN development, which may result from inhibiting adenine-induced TGF-β production accompanying oxidative stress and inflammation, as well as fibrogenesis. Our data imply that EA-enriched HLE regulates the TGF-β/Smad signaling, which in turn led to reduced renal mesangial cell injury and fibrosis in HN and provided a new mechanism for its nephroprotective activity.
高尿酸血症肾病（HN）是由沉积在肾脏中的尿酸盐晶体引起的，并导致肾纤维化。尿酸（UA）已被证实在HN的发病机制中直接导致肾系膜细胞氧化应激和纤维化。一些抗氧化剂可作为HN的化学预防剂。富含多酚的叶提取物（HLE）已被证明具有降血糖、抗氧化、降血脂、抗动脉粥样硬化和抗癌作用。本研究的目的是检测HLE及其主要成分鞣花酸（EA）对肾纤维化的抑制作用。结果表明，用UA预处理的小鼠肾小球系膜SV40MES13细胞出现明显的形态变化和活力丧失，并影响基质金属蛋白酶（MMPs）的活性。非细胞毒性剂量的HLE和EA消除了UA诱导的细胞损伤和MMP-2/9分泌。此外，HLE和EA对经UA处理的细胞具有抗氧化和抗炎作用，可减少转化生长因子-β（TGF-β）的产生。接下来，HLE或EA抑制了UA激活的促纤维化因子、细胞外基质（ECM）沉积和上皮-间质转化（EMT）。机制分析表明，HLE的抗纤维化作用可能通过TGF-β/Smad信号介导，Smad7 siRNA转染证实了这一点。此外，补充HLE和EA可显著减轻HN的发展，这可能是由于抑制了腺嘌呤诱导的伴随氧化应激、炎症以及纤维化形成的TGF-ββ产生。我们的数据表明，富含EA的HLE调节TGF-β/Smad信号，进而减少HN中肾系膜细胞损伤和纤维化，并为其肾保护活性提供了新机制。
