《生命科学》 2025, 37(2): 212-222

常染色体显性遗传性多囊肾病的研究进展

郭啸宇¹ , 白玉杰² , 孙　恺³ , 杨天民⁴ , 夏庆华^3,4,*

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

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Ca2+ 敏感的腺苷酸环化酶5 和6，导致环磷酸腺苷(cyclic adenosine monophosphate, cAMP) 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。

通讯作者：夏庆华 , Email:xiaqh2016@163.com

Research progress of autosomal dominant polycystic kidney disease

GUO Xiao-Yu¹ , BAI Yu-Jie² , SUN Kai³ , YANG Tian-Min⁴ , XIA Qing-Hua^3,4,*

¹School of Life Sciences, Shandong Normal University, Jinan 250307, China ²Shandong Jingwei Biotechnology Co., Ltd., Weifang 261000, China ³Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China ⁴Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China

Abstract:

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 Ca2+ sensitive adenylate cyclase 5 and 6 and increase cyclic adenosine monophosphate (cAMP) , 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.

Communication Author：XIA Qing-Hua , Email:xiaqh2016@163.com