Notch2 Inhibition and Kidney Cyst Growth in Autosomal Dominant Polycystic Kidney Disease

被引:0
作者
Ren, Huiwen [1 ]
Mu, Chengsen [1 ]
Wang, Yuhan [1 ]
Cheng, Yuanyuan [1 ]
Hou, Yayan [1 ]
Li, Yizhe [1 ]
Liu, Na [1 ]
Yin, Zhuming [2 ]
Xiong, Hui [3 ]
Chen, Yupeng [4 ]
Yang, Tianxin [5 ,6 ]
Yu, Ying [1 ]
Shen, Yujun [1 ]
机构
[1] Tianjin Med Univ, Prov & Minist Cosponsored Collaborat Innovat Ctr M, Tianjin Key Lab Inflammatory Biol, Sch Basic Med Sci,Ctr Cardiovasc Dis,Dept Pharmaco, Tianjin, Peoples R China
[2] Tianjin Med Univ, Tianjin Med Univ Canc Inst & Hosp, Sino Russian Joint Res Ctr Oncoplast Breast Surg, Natl Clin Res Ctr Canc,Minist Educ,Tianjins Clin R, Tianjin, Peoples R China
[3] Shandong First Med Univ, Shandong Prov Hosp, Dept Urol, Jinan, Peoples R China
[4] Tianjin Med Univ, Sch Basic Med Sci, Prov & Minist Cosponsored Collaborat Innovat Ctr M, Dept Biochem & Mol Biol,Key Lab Immune Microenviro, Tianjin, Peoples R China
[5] Univ Utah, Dept Internal Med, Salt Lake City, UT USA
[6] Vet Affairs Med Ctr, Salt Lake City, UT USA
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2025年
基金
中国国家自然科学基金;
关键词
polycystic kidney disease; HAJDU-CHENEY-SYNDROME; TRANSCRIPTION FACTORS; ETS FAMILY; FACTOR EHF; CELL; PATHWAYS; EXPRESSION; ADHESION; BIOLOGY; HES-1;
D O I
10.1681/ASN.0000000592
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Key PointsNotch2 activation promotes kidney cyst growth.Silencing Notch2 ameliorated cyst growth in mice with autosomal dominant polycystic kidney disease.BackgroundNotch 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.MethodsWe 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.ResultsNotch2 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 NOTCH2 (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.ConclusionsNotch2 signaling promoted kidney cyst growth, partially by upregulating Ehf expression.
引用
收藏
页码:781 / 797
页数:17
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