淫羊藿苷通过Cx32-Nox4信号通路改善高血压肾纤维化和损伤  

Icariin improves hypertensive renal fibrosis and injury through Cx32-Nox4 signaling pathway

作　　者：吴笑雪 叶益平 雷振东 张尊敬[3] 陈文霖[4] WU Xiaoxue;YE Yiping;LEI Zhendong;ZHANG Zunjing;CHEN Wenling(Department of Traditional Chinese Medicine,Lishui Hospital of Traditional Chinese Medicine,Lishui 323000,Zhejiang,China;Department of Oncology,Lishui 323000,Zhejiang,China;Department of Geriatrics,Lishui 323000,Zhejiang,China;Department of Respiratory Medicine,Lishui 323000,Zhejiang,China;Lishui Central Hospital,Lishui 323000,Zhejiang,China)

机构地区：[1]浙江中医药大学附属丽水中医院老年病科,浙江丽水323000 [2]浙江中医药大学附属丽水中医院中医肿瘤科,浙江丽水323000 [3]浙江中医药大学附属丽水中医院呼吸内科,浙江丽水323000 [4]浙江中医药大学附属丽水中医院心血管内科,浙江丽水323000

出　　处：《中国临床药理学与治疗学》2024年第8期870-878,共9页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：丽水市科学技术局(2021SJZC036)。

摘　　要：目的:探讨淫羊藿苷通过Cx32-Nox4信号通路对高血压肾纤维化和损伤的影响。方法:在自发性高血压大鼠(spontaneously hypertensive rats,SHRs)上建立高血压肾病(hypertensive nephropathy,HN)大鼠模型。实验分为4组:正常对照组(WKY大鼠)、模型组(SHR)、淫羊藿苷10 mg·kg^(-1)·d^(-1)组(每天灌胃淫羊藿苷一次)、淫羊藿苷30 mg·kg^(-1)·d^(-1)组(每天灌胃淫羊藿苷一次),每组10只。在体内检测纤维化相关蛋白的表达。选择暴露于血管紧张素Ⅱ(AngⅡ)的NRK-52E细胞来观察淫羊藿苷对肾损伤的影响。用蛋白质免疫印迹法和免疫组化检测细胞外基质(extracellular matrix,ECM)的水平,包括α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)、Ⅰ型胶原(collagenⅠ,Col-Ⅰ)和纤连蛋白(fibronectin,FN)的表达。试剂盒检测氧化应激标记物超氧化物歧化酶(superoxide dismutase,SOD)和丙二醛(malondialdehyde,MDA)表达的变化。结果:淫羊藿苷在体内显著降低SHR大鼠的肾脏纤维化。淫羊藿苷下调α-SMA、FN和Col-Ⅰ的表达(P<0.05),并保护高血压损伤的肾组织免受进行性纤维化的影响。淫羊藿苷可以显著提高SHR大鼠肾脏和血清中的总SOD活性,显著降低MDA水平(P<0.05)。此外,淫羊藿苷显著提高SHR大鼠肾脏中Cx32的表达,并显著减少Nox4的表达(P<0.05)。淫羊藿苷对AngⅡ介导的NRK-52E细胞损伤和纤维化具有保护作用。结论:淫羊藿苷可以改善肾小管间质纤维化并延缓HN的进展。肾脏保护可能归因于Cx32-Nox4信号通路介导的氧化应激的调节来实现。AIM:To investigate the effect of icariin on renal fibrosis and injury in hypertension through Cx32-Nox4 signaling pathway.METHODS:Models of hypertensive nephropathy(HN)were established in spontaneously hypertensive rats(SHRs).The experiment was divided into 4 groups:normal control group(WKY rats),model group(SHR),icariin 10 mg·kg^(-1)·d^(-1)group(icariin once daily),icariin 30 mg·kg^(-1)·d^(-1)group(icariin once daily),n=10.The expression of fibrosis-related proteins was detected in vivo.NRK-52E cells exposed to AngⅡwere selected to observe the effects of icariin on kidney injury.Extracellular matrix(ECM)levels,includingα-smooth muscle actin(α-SMA),collagenⅠ(Col-I)and fibronectin(FN)expression were measured by Western blot and immunohistochemistry.The expressions of oxidative stress markers including superoxide dismutase(SOD)and malondialdehyde(MDA)were determined by the test kit.RE-SULTS:Icariin reduced renal fibrosis in SHR rats in vivo.Icariin down-regulated the expression ofα-SMA,FN,and Col-Ⅰand protected hypertensiondamaged kidney tissue from progressive fibrosis(P<0.05).Icariin increased the total SOD activity and decrease the MDA level in kidney and serum of SHR rats(P<0.05).In addition,icariin increased the expression of Cx32 and decreased the expression of Nox4 in the kidneys of SHR rats(P<0.05).Icariin had a protective effect on AngⅡ-mediated NRK-52E cell damage and fibrosis.CONCLUSION:Icariin can improve renal tubulointerstitial fibrosis and delay the progression of HN.Renal protection may be attributed to the regulation of oxidative stress mediated by the Cx32-Nox4 signaling pathway.

关 键 词：淫羊藿苷 Cx32-Nox4信号通路 高血压肾病 肾纤维化 肾损伤 

分 类 号：R965.2[医药卫生—药理学]