Ren Huiwen, Mu Chengsen, Wang Yuhan, Cheng Yuanyuan, Hou Yayan, Li Yizhe, Liu Na, Yin Zhuming, Xiong Hui, Chen Yupeng, Yang Tianxin, Yu Ying, Shen Yujun
Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Department of Breast Oncoplastic Surgery, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Ministry of Education, Tianjin's Clinical Research Center for Cancer, Sino-Russian Joint Research Center for Oncoplastic Breast Surgery, Tianjin Medical University, Tianjin, China.
J Am Soc Nephrol. 2025 May 1;36(5):781-797. doi: 10.1681/ASN.0000000592. Epub 2025 Jan 2.
Notch2 activation promotes kidney cyst growth. Silencing Notch2 ameliorated cyst growth in mice with autosomal dominant polycystic kidney disease.
Notch signaling, a conserved mechanism of cell-to-cell communication, plays a crucial role in regulating cellular processes, such as proliferation and differentiation, in a context-dependent manner. However, the specific contribution of Notch signaling to the progression of polycystic kidney disease (PKD) remains unclear.
We investigated the changes in Notch signaling activity (Notch1–4) in the kidneys of patients with autosomal dominant PKD (ADPKD) and two ADPKD mouse models (early and late onset). Multiple genetic and pharmacologic approaches were used to explore Notch2 signaling during kidney cyst formation in PKD.
Notch2 expression was significantly increased in the kidney tissues of patients with ADPKD and ADPKD mice. Targeted expression of Notch2 intracellular domain in renal epithelial cells resulted in cyst formation and kidney failure in neonatal and adult mice. Mechanistically, Notch2/Hey2 signaling promoted renal epithelial cell proliferation by driving the expression of the E26 transformation–specific homologous factor (Ehf). Depletion of Ehf delayed Notch2 intracellular domain overexpression–induced cyst formation and kidney failure in mice. A gain-of-function mutation in exon 34 of (c.6426dupT), which caused PKD in patients with Hajdu–Cheney syndrome, accelerated cell growth in cultured human renal epithelial cells by activating HEY2/EHF signaling. Finally, ablation of Notch2 or treatment of a kidney-targeting nanoparticle carrying the liposome/Notch2–small interfering RNA complex, significantly suppressed kidney cyst growth in early-onset ADPKD mice.
Notch2 signaling promoted kidney cyst growth, partially by upregulating Ehf expression.
Notch2激活促进肾囊肿生长。沉默Notch2可改善常染色体显性多囊肾病小鼠的囊肿生长。
Notch信号是一种保守的细胞间通讯机制，在以依赖于上下文的方式调节细胞过程（如增殖和分化）中起关键作用。然而，Notch信号对多囊肾病（PKD）进展的具体贡献仍不清楚。
我们研究了常染色体显性PKD（ADPKD）患者和两种ADPKD小鼠模型（早发和晚发）肾脏中Notch信号活性（Notch1-4）的变化。采用多种基因和药理学方法探索PKD肾囊肿形成过程中的Notch2信号。
ADPKD患者和ADPKD小鼠的肾组织中Notch2表达显著增加。在肾上皮细胞中靶向表达Notch2细胞内结构域导致新生和成年小鼠出现囊肿形成和肾衰竭。机制上，Notch2/Hey2信号通过驱动E26转化特异性同源因子（Ehf）的表达促进肾上皮细胞增殖。Ehf的缺失延迟了Notch2细胞内结构域过表达诱导的小鼠囊肿形成和肾衰竭。（c.6426dupT）外显子34中的功能获得性突变导致Hajdu-Cheney综合征患者发生PKD，通过激活HEY2/EHF信号加速培养的人肾上皮细胞的生长。最后，Notch2的缺失或携带脂质体/Notch2小干扰RNA复合物的肾靶向纳米颗粒的治疗显著抑制了早发ADPKD小鼠的肾囊肿生长。
Notch2信号促进肾囊肿生长，部分是通过上调Ehf表达实现的。
