1,4,5-三磷酸肌醇受体3促进常染色体显性遗传性多囊肾病囊泡生长  

Inositol 1,4,5-triphosphate receptor 3 promotes renal cyst development in autosomal dominant polycystic kidney disease

作　　者：邱志维 刘明 周虹[1] 杨宝学[1] QIU Zhi-Wei;LIU Ming;ZHOU Hong;YANG Bao-Xue(State Key Laboratory of Vascular Homeostasis and Remodeling,Department of Pharmacology,School of Basic Medical Sciences,Peking University,Beijing 100191,China)

机构地区：[1]北京大学基础医学院药理学系,血管稳态与重构全国重点实验室,北京100191

出　　处：《生理学报》2023年第3期328-338,共11页Acta Physiologica Sinica

基　　金：supported by the National Natural Science Foundation of China(No.81974083,82273999);the Beijing Natural Science Foundation(No.7212151);the grant from the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2022-JKCS-15)。

摘　　要：本文旨在阐明1,4,5-三磷酸肌醇受体3(inositol 1,4,5-trisphosphate receptor 3,IP_(3)R3)在常染色体显性遗传性多囊肾病(autosomal dominant polycystic kidney disease,ADPKD)肾囊泡发生、发展过程中的作用,为ADPKD的治疗提供理论基础。使用2-氨基乙氧基二苯基硼酸盐(2-aminoethoxy-diphenyl borate,2-APB)和shRNA抑制IP_(3)R3的表达水平,通过MDCK(MadinDarby canine kidney)囊泡模型、胚胎肾囊泡模型、肾脏特异性Pkd1敲除(PKD)小鼠模型探究IP_(3)R3在囊泡生长过程中的作用,并通过Western blot、免疫荧光染色技术探究IP_(3)R3调控囊泡生长的分子机制。结果显示,在PKD小鼠肾脏中,IP_(3)R3的表达水平显著升高。在胚胎肾囊泡模型和MDCK囊泡模型中,通过2-APB或shRNA抑制IP_(3)R3的表达可显著延缓囊泡的生长。机制研究结果显示,在ADPKD肾囊泡生长过程中,异常活化的cAMP-PKA信号通路促进了IP_(3)R3的表达,并促进其从内质网向细胞间连接处转运。IP_(3)R3的上调以及亚细胞定位的异常激活MAPK和mTOR信号通路,加速细胞周期,引起囊泡上皮细胞异常增殖,最终促进囊泡的生长。上述结果提示,IP_(3)R3在促进ADPKD肾囊泡生长过程中发挥重要作用,抑制IP_(3)R3的表达及亚细胞再分布过程可以有效延缓囊泡的生长,而IP_(3)R3有望成为ADPKD的治疗靶点。The purpose of the present study was to determine the role of inositol 1,4,5-trisphosphate receptor 3(IP_3R3)in renal cyst development in autosomal dominant polycystic kidney disease(ADPKD).2-aminoethoxy-diphenyl borate(2-APB)and shRNA were used to suppress the expression of IP_3R3.The effect of IP_(3R3)on cyst growth was investigated in Madin-Darby canine kidney(MDCK)cyst model,embryonic kidney cyst model and kidney specific Pkd1 knockout(PKD)mouse model.The underlying mechanism of IP_(3R3)in promoting renal cyst development was investigated by Western blot and immunofluorescence staining.The results showed that the expression level of IP_(3R3)was significantly increased in the kidneys of PKD mice.Inhibiting IP_(3R3)by 2-APB or shRNA significantly retarded cyst expansion in MDCK cyst model and embryonic kidney cyst model.Western blot and immunofluorescence staining results showed that hyperactivated cAMP-PKA signaling pathway in the growth process of ADPKD cyst promoted the expression of IP_3R3,which was accompanied by a subcellular redistribution process in which IP_(3R3)was translocated from endoplasmic reticulum to intercellular junction.The abnormal expression and subcellular localization of IP_(3R3)further promoted cyst epithelial cell proliferation by activating MAPK and mTOR signaling pathways and accelerating cell cycle.These results suggest that the expression and subcellular distribution of IP_(3R3)are involved in promoting renal cyst development,which implies IP_(3R3)as a potential therapeutic target of ADPKD.

关 键 词：常染色体显性遗传性多囊肾病 1 4 5-三磷酸肌醇受体3 细胞周期 细胞增殖 

分 类 号：R692[医药卫生—泌尿科学]