常染色体显性遗传性多囊肾病的研究进展  

Research progress of autosomal dominant polycystic kidney disease

作　　者：郭啸宇 白玉杰 孙恺 杨天民 夏庆华[3,4] GUO Xiao-Yu;BAI Yu-Jie;SUN Kai;YANG Tian-Min;XIA Qing-Hua(School of Life Sciences,Shandong Normal University,Jinan 250307,China;Shandong Jingwei Biotechnology Co.,Ltd.,Weifang 261000,China;Department of Urology,Shandong Provincial Hospital Affiliated to Shandong University,Jinan 250021,China;Department of Urology,Shandong Provincial Hospital Affiliated to Shandong First Medical University,Jinan 250021,China)

机构地区：[1]山东师范大学生命科学学院,济南250307 [2]山东荆卫生物科技有限公司,潍坊261000 [3]山东大学附属省立医院(山东省立医院)泌尿外科,济南250021 [4]山东第一医科大学附属省立医院(山东省立医院)泌尿外科,济南250021

出　　处：《生命科学》2025年第2期212-222,共11页Chinese Bulletin of Life Sciences

摘　　要：常染色体显性遗传性多囊肾病(autosomal dominant polycystic kidney disease,ADPKD)是肾功能衰竭的主要原因之一。ADPKD是一种常见的单基因遗传性疾病,通常由编码多囊蛋白1(polycystin 1,PC1)或多囊蛋白2(PC2)的Pkd1基因和Pkd2基因突变引起。PC1或PC2功能丧失导致细胞质钙减少,激活Ca^(2+)敏感的腺苷酸环化酶5和6,导致环磷酸腺苷(cyclic adenosine monophosphate,c AMP)水平升高,进一步导致B-Raf/MEK/ERK和CREB/AREG/EGFR通路激活,并通过ERK使TSC1/TSC2复合物失活,激活mTOR信号,促进ADPKD细胞增殖。目前,基因检测技术为ADPKD临床诊断提供了更明确的诊断和预后信息,有助于改善患者的临床管理。托伐普坦是目前唯一获得FDA批准的ADPKD药物,但它无法治愈ADPKD的遗传缺陷。最新研究显示,ADPKD囊肿形成是可逆的,PC1重新表达导致ADPKD快速逆转,且转基因表达PC1 C末端最后200 aa短片段足以抑制囊性表型并保留肾功能,这为探索ADPKD基因治疗策略打开了大门。此外,类器官模型提供了一个准确且可重复的平台,有助于ADPKD疾病机制的研究和药物发现。Autosomal dominant polycystic kidney disease(ADPKD)is one of the main causes of renal failure.ADPKD is a common monogenic inherited disease,usually caused by mutations in the pkd 1 gene and/or pkd 2 gene encoding polycystin 1(PC1)or polycystin 2(PC2).Loss of PC1 and/or PC2 function results in reduced cytoplasmic calcium,which may activate Ca^(2+)sensitive adenylate cyclase 5 and 6 and increase cyclic adenosine monophosphate(c AMP),further leading to activation of B-Raf/MEK/ERK and CREB/AREG/EGFR pathways,and inactivation of TSC1/TSC2 complex through ERK,stimulating mTOR signaling and promoting ADPKD cell proliferation.Current genetic testing techniques provide more definite clinical diagnostic and prognostic information for ADPKD and can help to improve the clinical management of patients.Tolvaptan is currently the only FDAapproved ADPKD drug,but it can not cure the genetic defect in ADPKD.Recent studies shows that re-expression of PC1 leads to rapid reversion of ADPKD.Transgenic expression of the last short 200 amino acids at the C end of PC1 is sufficient to suppress the cystic phenotype and preserve renal function,opening the door to exploring ADPKD gene therapy strategies.Furthermore,organoid models provide an accurate and reproducible platform to facilitate disease mechanistic research and drug discovery in ADPKD.

关 键 词：多囊肾病 常染色体显性遗传性多囊肾病 PKD1基因 多囊蛋白1 基因检测 

分 类 号：Q291[生物学—细胞生物学] R692[医药卫生—泌尿科学]