ANKHD1通过细胞周期蛋白D1/细胞周期蛋白依赖性激酶4途径促进常染色体显性多囊肾病中的致病性增殖。

ANKHD1 promotes pathogenic proliferation in Autosomal Dominant Polycystic Kidney Disease via the Cyclin D1/CDK4 pathway.

作者信息

Terzenidou Maria-Eirini, Patera Foteini, Macleod Fiona M, Ong Albert C M, Fragiadaki Maria

机构信息

William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, UK.

Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, UK.

出版信息

J Transl Med. 2025 Jun 2;23(1):612. doi: 10.1186/s12967-025-06359-9.

BACKGROUND

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic cause of renal failure. Uncontrolled proliferation drives ADPKD, which manifests with cystic kidney enlargement. Yet, the mechanisms by which renal epithelial cells lose cell cycle control are largely unknown. To investigate this, we examined the expression and function of the Ankyrin Repeat and single KH Domain 1 (ANKHD1), which positively regulates proliferation in cancer, yet its role in ADPKD is unexplored.

RESULTS

We report elevated proliferation (Ki67 and Cyclin D1) in three independent mouse models of ADPKD, the , the and the . We find that ANKHD1 protein localises in cyst lining cells of both aquaporin-1 and 2 (AQP1-AQP2) positive cysts. ANKHD1 knockdown in human cells or knockout in mouse tissues resulted in reduced proliferation, slower cystic growth in vitro and smaller kidneys in vivo; ultimately leading to improved renal function. Mechanistically, ANKHD1 binds to CDK4 and positively controls the Cyclin D1/CDK4 pathway. ANKHD1-mediated enhancement of Cyclin D1/CDK4 activity leads to increased retinoblastoma phosphorylation and proliferation, a mechanism that is p19-dependent but p21 independent.

CONCLUSIONS

We report a functional role for ANKHD1 in driving pathogenic proliferation in ADPKD via the Cyclin D1/CDK4 axis.

背景

常染色体显性多囊肾病（ADPKD）是肾衰竭最常见的遗传病因。不受控制的增殖驱动ADPKD，表现为肾囊肿性增大。然而，肾上皮细胞失去细胞周期控制的机制在很大程度上尚不清楚。为了研究这一问题，我们检测了锚蛋白重复序列和单KH结构域1（ANKHD1）的表达和功能，ANKHD1在癌症中正向调节增殖，但其在ADPKD中的作用尚未得到探索。

结果

我们报告在三种独立的ADPKD小鼠模型（分别为[此处原文缺失相关模型名称]、[此处原文缺失相关模型名称]和[此处原文缺失相关模型名称]）中增殖（Ki67和细胞周期蛋白D1）升高。我们发现ANKHD1蛋白定位于水通道蛋白1和2（AQP1-AQP2）阳性囊肿的囊肿衬里细胞中。在人类细胞中敲低ANKHD1或在小鼠组织中敲除ANKHD1导致增殖减少、体外囊肿生长减慢以及体内肾脏变小；最终导致肾功能改善。从机制上讲，ANKHD1与细胞周期蛋白依赖性激酶4（CDK4）结合并正向控制细胞周期蛋白D1/CDK4通路。ANKHD1介导的细胞周期蛋白D1/CDK4活性增强导致视网膜母细胞瘤磷酸化增加和增殖，这一机制依赖于p19但不依赖于p21。