Inhibition of Hedgehog signaling does not mitigate polycystic kidney disease severity in a Pkd1 mutant mouse model.

IF 3.3 3区 生物学 Q3 CELL BIOLOGY
Sean Gombart, Scott Houghtaling, Tzu-Hua Ho, David R Beier
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引用次数: 0

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a monogenic disorder caused by mutations in PKD1 or PKD2, encoding polycystin-1 and polycystin-2, respectively. These polycystins form a cilia-localized complex that, when mutated, fails to inhibit an uncharacterized cilia-dependent cyst activation (CDCA) signal. This leads to progressive bilateral cyst growth and ultimately compromised renal function. Previous in vitro and in vivo studies from our group demonstrated that Hedgehog (Hh) signaling inhibition reduced renal cystic severity in PKD models. To further investigate, we inactivated several Hh pathway components (Gli1, Gli2, Gli3, Smo) in a Pkd1 hypomorphic mouse model through conditional deletion by tamoxifen-induced Cre-Lox recombination. We assessed cystic severity using kidney weight assessment and a microCT-based 3D imaging assay. Contrary to expectations, inactivation of Gli1 and Smo significantly increased cystogenesis. These findings suggest that Hh signaling does not mediate the CDCA signal.

在Pkd1突变小鼠模型中,抑制刺猬信号传导不能减轻多囊肾病的严重程度。
常染色体显性多囊肾病(ADPKD)是由分别编码多囊蛋白1和多囊蛋白2的PKD1或PKD2突变引起的单基因疾病。这些多囊毒素形成一种纤毛定位复合物,当发生突变时,不能抑制非特征的纤毛依赖性囊肿激活(CDCA)信号。这导致进行性双侧囊肿生长,最终损害肾功能。我们小组之前的体外和体内研究表明,Hedgehog (Hh)信号抑制降低了PKD模型中肾囊的严重程度。为了进一步研究,我们通过他莫昔芬诱导的Cre-Lox重组条件缺失,在Pkd1亚型小鼠模型中失活了几个Hh通路组分(Gli1, Gli2, Gli3, Smo)。我们使用肾脏重量评估和基于微ct的3D成像分析来评估囊性囊肿的严重程度。与预期相反,Gli1和Smo的失活显著增加了膀胱发生。这些发现表明Hh信号不介导CDCA信号。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of cell science
Journal of cell science 生物-细胞生物学
CiteScore
7.30
自引率
2.50%
发文量
393
审稿时长
1.4 months
期刊介绍: Journal of Cell Science publishes cutting-edge science, encompassing all aspects of cell biology.
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