PKD1 deficiency induces Bronchiectasis in a porcine ADPKD model

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.

Automated summary

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent genetic disorder characterized by the development of renal cysts. This study investigates the relationship between ADPKD and bronchiectasis in a PKD1(+/-) pig model. Methods: The study assesses phenotypic changes in airway epithelial and mesenchymal cells in PKD1(+/-) pigs and explores the molecular mechanisms underlying these changes using PKD1(+/-) pig lungs, human mesenchymal cells, and PKD1 deficient human epithelial cells. Result: The study identifies bronchiectasis in PKD1(+/-) pigs, consistent with clinical symptoms in ADPKD patients. The deficiency of PKD1 disrupts the airway epithelial barrier, leading to an inflammatory response and airway smooth muscle cell remodeling, ultimately resulting in bronchiectasis. Conclusion: This study provides important insights into the pathogenesis of bronchiectasis in ADPKD and highlights PKD1 as a potential target for diagnosis and treatment strategies.