Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.