依普利酮对慢性肾脏病妊娠大鼠梗阻对侧肾组织的保护作用  

Eplerenone protects contralateral kidney tissue from obstruction in pregnant rats with chronic kidney disease

作　　者：许畅 许庆友 周文平 牛洁琪 熊云昭 王洪双 张孟娟 刘佳志 钟艳 王香婷 王筝 XU Chang;XU Qing-you;ZHOU Wen-ping;NIU Jie-qi;XIONG Yun-zhao;WANG Hong-shuang;ZHANG Meng-juan;LIU Jia-zhi;ZHONG Yan;WANG Xiang-ting;WANG Zheng(College of Graduate,Hebei University of Chinese Medicine,Shijiazhuang 050091,China;College of Integrated Traditional Chinese and Western Medicine,Hebei University of Traditional Chinese Medicine Shijiazhuang 050200,China;Hebei Key Laboratory of Liver and Kidney Diseases of Integrated Traditional Chinese and Western Medicine,Shijiazhuang 050091,China;College of Basic Medicine,Hebei University of Traditional Chinese Medicine,Shijiazhuang 050200,China)

机构地区：[1]河北中医药大学研究生学院,河北石家庄050091 [2]河北中医药大学中西医结合学院,河北石家庄050200 [3]河北省中西医结合肝肾病证研究重点实验室,河北石家庄050091 [4]河北中医药大学基础医学院,河北石家庄050200

出　　处：《中国药理学通报》2023年第8期1534-1540,共7页Chinese Pharmacological Bulletin

基　　金：河北省自然科学基金资助项目(No H2021423006);河北省研究生创新项目(No XCXZZSS2022010)。

摘　　要：目的研究依普利酮对慢性肾脏病妊娠大鼠梗阻对侧肾脏的保护作用及机制。方法雌性未经产Wistar大鼠随机分为假手术组、假手术妊娠组、模型组、依普利酮组。模型组和依普利酮组大鼠结扎单侧输尿管,术后d 2开始给药,依普利酮组给予依普利酮100 mg·kg^(-1)·d^(-1)治疗。术后八周将假手术妊娠组、模型组和依普利酮组雌鼠与♂大鼠合笼,制备慢性肾脏病妊娠大鼠模型,妊娠d 19摘取梗阻对侧肾脏。HE、Masson染色观察肾脏病理改变;免疫组化、Western blot及Real-time PCR观察α-平滑肌肌动蛋白(α-SMA)、Ⅰ型胶原(Collagen Ⅰ)、淋巴内皮透明质酸受体1(LYVE-1)、血管内皮生长因子C(VEGF-C)、血管内皮生长因子受体3(VEGFR-3)、盐皮质激素受体(MR)、血清和糖皮质激素诱导性蛋白激酶1(SGK-1)、磷酸化核因子κB(p-NF-κB)的表达。结果肾脏病理显示模型组大鼠炎性细胞浸润增多,胶原纤维沉积增多;α-SMA、Collagen Ⅰ、LYVE-1、VEGF-C、VEGFR-3、MR、SGK-1、p-NF-κB蛋白或mRNA表达增强(P<0.01),依普利酮可下调其表达(P<0.01或P<0.05)。结论依普利酮可保护慢性肾脏病妊娠大鼠梗阻对侧肾脏,其机制可能与阻断醛固酮与MR结合,改善淋巴管生成,阻断SGK-1/NF-κB信号通路有关。Aim To study the protective effect of eplerenone on the contralateral kidney in pregnant rats with chronic kidney disease(CKD)and its mechanism.Methods Female Wistar rats were randomly divided into sham-operation group,sham-operation pregnancy group,model group and eplerenone group.The rats in the model group and eplenone group had ligation unilateral ureter,and the rats in the eplenone group were treated with 100 mg·kg^(-1)·d^(-1).Eight weeks after UUO surgery,female mice in estrous cycle in the sham pregnancy group,model group and eplerenone group were caged with male rats to prepare a pregnant rat model of chronic kidney disease.On the 19th day of gestation,the obstructed kidney was removed.HE and Masson staining were used to observe the pathological changes of renal tissues.Immunohistochemistry,Western blot and Real-time PCR were employed to observe the expression ofα-smooth muscle actin(α-SMA),collagen type I(collagen Ⅰ),lymphoendothelial hyaluronic acid receptor 1(LYVE-1),vascular endothelial growth factor C(VEGF-C),vascular endothelial growth factor receptor 3(VEGFR-3),mineralocorticoid receptor(MR),serum and glucocorticoid protein kinase 1(SGK-1)and phosphorylation nuclear factor κB(p-NF-κB).Results Renal pathology showed increased inflammatory cell infiltration and collagen fiber deposition in model group.The expressions of α-SMA,Collagen Ⅰ,LYVE-1,VEGF-C,VEGFR-3,MR,SGK-1 and p-NF-κB protein or mRNA in model group were increased(P<0.01),while the expressions of eplenone group were down-regulated(P<0.01 or P<0.05).Conclusions Eplerenone has protective effect on the contralateral kidney of pregnant rats with chronic kidney disease.The mechanism may be related to blocking the binding of aldosterone and MR,improving lymphangiogenesis and blocking SGK-1/NF-κB signaling pathway.

关 键 词：妊娠 慢性肾脏病 淋巴管生成 肾纤维化 依普利酮 梗阻对侧肾 SGK-1/NF-κB信号通路 

分 类 号：R-332[医药卫生] R322.61R692R714.25R977.1R983.1