Quercetin inhibits renal cyst growth in vitro and via parenteral injection in a polycystic kidney disease mouse model
Quercetin inhibits renal cyst growth in vitro and via parenteral injection in a polycystic kidney disease mouse model
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槲皮素在体外和通过肠胃外注射抑制多囊肾病小鼠模型中的肾囊肿生长
DOI：
10.1039/c7fo01253e
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发表时间：
2018
期刊：
影响因子：
6.1
通讯作者：
Sun Ying
中科院分区：
文献类型：
--
作者：
Zhu Yangyang;Teng Tian;Wang Hu;Guo Hao;Du Lei;Yang Baoxue;Yin Xiaoxing;Sun Ying
常染色体显性遗传性多囊肾病（ADPKD）是一种常见的单基因疾病，其特征是肾脏中充满液体的囊肿大量增大。目前迫切需要开发有效的ADPKD治疗方法。我们使用体外Madin-Darby犬肾（MDCK）囊肿模型和小鼠胚胎肾囊肿模型来评估槲皮素是否抑制囊肿的发育。然后，我们使用多囊肾病（PKD）小鼠模型，通过皮下注射进一步确定槲皮素（100 mg/kg体重，每天两次）对PKD小鼠的体内作用。结果显示，槲皮素显著地且剂量依赖性地抑制MDCK囊肿和胚胎肾囊肿模型中的囊肿形成和扩大。槲皮素还显著降低PKD小鼠的囊性指数。有效剂量的槲皮素对MDCK细胞无毒性作用。槲皮素处理降低了PKD小鼠肾脏中细胞内信号蛋白的水平，包括磷酸化蛋白激酶B（也称为AKT）和磷酸化细胞外信号调节激酶（ERK），这些蛋白在ADPKD中上调并促进囊肿发育。槲皮素还逆转E-钙粘蛋白的表达，其定位于PKD小鼠肾脏的正常近端小管中。总之，这些结果表明，槲皮素在体内和体外阻碍肾囊肿的发展，并代表了一种新的候选策略，用于治疗ADPKD。
Autosomal dominant polycystic kidney disease (ADPKD) is a common monogenic disease characterized by massive enlargement of fluid-filled cysts in the kidney. There is an urgent need to develop effective ADPKD therapies. We used an in vitro Madin–Darby canine kidney (MDCK) cyst model and a murine embryonic kidney cyst model to evaluate whether quercetin inhibits cyst development. We then used a polycystic kidney disease (PKD) mouse model to further determine the in vivo effects of quercetin (100 mg per kg body weight twice per day) on PKD mice via subcutaneous injections. The results show that quercetin significantly and dose-dependently inhibited cyst formation and enlargement in the MDCK cyst and embryonic kidney cyst models. Quercetin also noticeably reduced the cystic index in PKD mice. Furthermore, the effective dose of quercetin did not cause cytotoxicity in MDCK cells. Quercetin treatment decreased the levels of intracellular signalling proteins in PKD mouse kidneys, including phosphorylated protein kinase B (also known as AKT) and phosphorylated extracellular signal-regulated kinase (ERK), which are upregulated and promote cyst development in ADPKD. Quercetin also reversed E-cadherin expression, which is localized in normal proximal tubules in PKD mouse kidneys. Taken together, these results demonstrate that quercetin hinders renal cyst development in vivo and in vitro and represents a novel candidate strategy for the treatment of ADPKD.