(Pro)renin receptor regulates lung development via the Wnt/β-catenin signaling pathway
(Pro)renin receptor regulates lung development via the Wnt/β-catenin signaling pathway
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(Pro) 肾素受体通过 Wnt/β-catenin 信号通路调节肺发育
DOI：
10.1152/ajplung.00295.2018
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发表时间：
2019-08-01
影响因子：
4.9
通讯作者：
Peng, Hua
中科院分区：
文献类型：
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作者：
Liu, Jie;Zhou, Yafan;Peng, Hua
(PRO)肾素受体[(P)RR]与原肾素结合，激活肾素-血管紧张素系统，对许多不同器官系统的发育是必不可少的。(P)RR是否在肺发育中也起作用尚不清楚。免疫组织化学染色检测(P)RR在胚胎、出生后的时空分布。和成人的肺。我们建立了一只肺特异的(P)RR基因敲除小鼠[Foxd1(cre/+)-(P)RRflx/flx]，并用免疫组织化学和TUNEL染色评估了肺形态、细胞增殖和细胞凋亡的变化。(P)用siRNA抑制人支气管上皮细胞(HBECs)的(P)RR，然后用CCK-8比色法和流式细胞仪检测细胞的增殖和凋亡。用RT-PCR和Western blotting检测基因敲除后基因表达的变化。(P)RR在支气管上皮的杆状细胞中表达，并在发育过程中表达增加。肺特异性(P)RR基因敲除扰乱了分支形态发生，导致肺发育不全和新生儿死亡。这些缺陷与肺上皮细胞和间充质细胞的凋亡增加和增殖减少有关，并可能通过下调Wnt11、β-连环蛋白和Axin2的表达而起作用。(P)RR通过典型的Wnt/β-catenin信号调节肺发育，可能成为治疗肺发育不良的新靶点。
The (pro)renin receptor [(P)RR] binds to prorenin to activate the renin-angiotensin system and is essential for the development of many different organ systems. Whether the (P)RR also plays a role in lung development is unknown. Immunostaining was used to determine the spatial-temporal distribution of (P)RR in the embryonic, postnatal. and adult lungs. We created a lung-specific (P)RR knockout mouse [Foxd1(cre/+)-(P)RRflox/flox] and assessed changes in lung morphology, cell proliferation, and apoptosis using immunohistochemistry and TUNEL staining. (P)RR function was confirmed by using siRNA to knock down (P)RR in human bronchial epithelial cells (HBECs) and then using the CCK-8 assay and flow cytometry to assess cell proliferation and apoptosis. Gene expression changes after knockdown were assessed by RT-PCR and Western blotting. (P)RR is expressed in the club cells of the bronchial epithelium, and expression increases throughout development. Lung-specific (P)RR knockout disrupted branching morphogenesis, leading to lung hypoplasia and neonatal mortality. These defects were associated with increased apoptosis and decreased proliferation of the pulmonary epithelial and mesenchymal cells and may be mediated by downregulation of Wnt11, beta-catenin, and Axin2. (P)RR regulates lung development through canonical Wnt/beta-catenin signaling and may present a new target for strategies to treat lung hypoplasia.