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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

邱志维, 刘明, 周虹, 杨宝学^*

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

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, IP3R3)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IP3R3的表达水平，通过MDCK (Madin- Darby 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IP3R3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IP3R3调控囊泡生长的分子机制。结果显示，在PKD小鼠肾脏中，IP3R3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IP3R3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IP3R3的表达，并促进其从内质网向细胞间连接处转运。IP3R3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，IP3R3在促进ADPKD肾囊泡生长过程中发挥重要作用，抑制IP3R3的表达及亚细胞再分布过程可以有效延缓囊泡的生长，而IP3R3有望成为ADPKD的治疗靶点。

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

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

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

Abstract

The purpose of the present study was to determine the role of inositol 1,4,5-trisphosphate receptor 3 (IP3R3) 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 IP3R3. The effect of IP3R3 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 IP3R3 in promoting renal cyst development was investigated by Western blot and immunofluorescence staining. The results showed that the expression level of IP3R3 was significantly increased in the kidneys of PKD mice. Inhibiting IP3R3 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 IP3R3, which was accompanied by a subcellular redistribution process in which IP3R3 was translocated from endoplasmic reticulum to intercellular junction. The abnormal expression and subcellular localization of IP3R3 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 IP3R3 are involved in promoting renal cyst development, which implies IP3R3 as a potential therapeutic target of ADPKD.

Key words: autosomal dominant polycystic kidney disease; inositol 1,4,5-triphosphate receptor 3; cell cycle; cell proliferation

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通讯作者：杨宝学　　E-mail: baoxue@bjmu.edu.cn

引用本文：

邱志维, 刘明, 周虹, 杨宝学. 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[J]. 生理学报 2023; 75 (3): 328-338.

QIU Zhi-Wei, LIU Ming, ZHOU Hong, YANG Bao-Xue. Inositol 1,4,5-triphosphate receptor 3 promotes renal cyst development in autosomal dominant polycystic kidney disease. Acta Physiol Sin 2023; 75 (3): 328-338 (in Chinese with English abstract).