Wang Runming, Li Wenya, Dai Haiting, Zhu Mingli, Li Lingyu, Si Guohui, Bai Yilina, Wu Hanyu, Hu Xiaoxiang, Xing Yiming
State Key Laboratory for Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, P.R. China.
Respir Res. 2022 Oct 29;23(1):292. doi: 10.1186/s12931-022-02214-3.
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.
常染色体显性多囊肾病（ADPKD）是一种常见的遗传性疾病，主要特征是肾囊肿的形成以及各种肾外表现。先前的研究表明ADPKD与支气管扩张有关，但其致病机制尚不清楚。在先前的研究中，我们培育出了PKD1猪，以模拟囊肿形成的进展以及类似于ADPKD患者所见的生理改变。
通过组织学分析评估PKD1猪气道上皮细胞和间充质细胞的表型变化。利用PKD1猪肺、人间充质细胞以及培育PKD1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PKD1猪中发现了支气管扩张，这与ADPKD患者的临床症状一致。PKD1的缺陷抑制了气道上皮屏障中E-钙黏蛋白的表达，这加剧了侵袭并导致持续的炎症反应。在此过程中，细胞外基质（ECM）成分发生改变，这促使气道平滑肌细胞表型从收缩型转变为增殖型。对平滑肌细胞的影响导致气道重塑和支气管扩张的形成。
据我们所知，PKD1猪提供了首个概括ADPKD中支气管扩张发病机制的模型。PKD1在气道上皮中的作用提示了开发支气管扩张诊断和治疗新策略的潜在靶点。
