PKD1 deficiency induces Bronchiectasis in a porcine ADPKD model.
PKD1 deficiency induces Bronchiectasis in a porcine ADPKD model.
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DOI：
10.1186/s12931-022-02214-3
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发表时间：
2022-10-29
影响因子：
5.8
通讯作者：
中科院分区：
文献类型：
--
作者：
常染色体显性遗传性多囊肾病（ADPKD）是一种常见的遗传性疾病，主要特征是肾囊肿的发展，以及各种肾外表现。既往研究表明ADPKD与支气管扩张有关，但其发病机制尚不清楚。在以前的研究中，我们已经产生了PKD 1 +/−猪，以模拟囊肿形成的进展和与ADPKD患者相似的生理变化。通过组织学分析评估PKD 1 +/−猪中气道上皮细胞和间充质细胞的表型变化。通过使用PKD 1 +/−猪肺、人间充质细胞和产生PKD 1缺陷的人上皮细胞来研究驱动这些过程的分子机制。我们在PKD 1 +/−猪中发现了支气管扩张，这与ADPKD患者的临床症状一致。PKD 1的缺乏抑制了气道上皮屏障中E-钙粘蛋白的表达，从而加重了侵袭并导致了持续的炎症反应。在此过程中，细胞外基质（ECM）成分发生了变化，这有助于气道平滑肌细胞表型从收缩表型转换为增殖表型。对平滑肌细胞的影响导致气道重塑和支气管扩张的建立。据我们所知，PKD 1 +/−猪提供了第一个重现ADPKD支气管扩张发病机制的模型。PKD 1在气道上皮中的作用提示了开发诊断和治疗支气管扩张症的新策略的潜在靶点。在线版本包含补充材料，可通过10.1186/s12931-022-02214-3获得。
Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent genetic disorder, mainly characterized by the development of renal cysts, as well as various extrarenal manifestations. Previous studies have shown that ADPKD is related to bronchiectasis, while its pathogenic mechanism is unclear. In previous studies, we have generated the PKD1+/− pigs to simulate the progression of cyst formation and physiological alterations similar to those seen in ADPKD patients. Phenotypic changes to airway epithelial cell and mesenchymal cell in PKD1+/− pigs were assessed by histological analysis. The molecular mechanisms driving these processes were investigated by using PKD1+/− pig lungs, human mesenchymal cells, and generating PKD1 deficient human epithelial cells. We identified bronchiectasis in PKD1+/− pigs, which is consistent with the clinical symptoms in ADPKD patients. The deficiency of PKD1 suppressed E-cadherin expression in the airway epithelial barrier, which aggravated invasion and leaded to a perpetuated inflammatory response. During this process, extracellular matrix (ECM) components were altered, which contributed to airway smooth muscle cell phenotype switch from a contractile phenotype to a proliferative phenotype. The effects on smooth muscle cells resulted in airway remodeling and establishment of bronchiectasis. To our knowledge, the PKD1+/− pig provides the first model recapitulating the pathogenesis of bronchiectasis in ADPKD. The role of PKD1 in airway epithelial suggests a potential target for development of new strategies for the diagnosis and treatment of bronchiectasis. The online version contains supplementary material available at 10.1186/s12931-022-02214-3.
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影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
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