PKD1 deficiency induces Bronchiectasis in a porcine ADPKD model

Area of Science:

• Genetics and Molecular Biology
• Pulmonology
• Nephrology

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder causing kidney cysts and other issues.
• Previous research suggests a connection between ADPKD and bronchiectasis, but the underlying mechanisms remain unknown.
• PKD1^+/- pigs were developed to model ADPKD's cyst progression and physiological changes.

Purpose of the Study:

• To investigate the pathogenic mechanism linking ADPKD to bronchiectasis.
• To analyze phenotypic and molecular changes in airway cells of PKD1^+/- pigs.
• To establish a preclinical model for studying ADPKD-associated bronchiectasis.

Main Methods:

• Histological analysis of airway epithelial and mesenchymal cells in PKD1^+/- pigs.
• Molecular investigation using PKD1^+/- pig lungs, human mesenchymal cells, and PKD1-deficient human epithelial cells.
• Assessment of E-cadherin expression and extracellular matrix alterations.

Main Results:

• Bronchiectasis was identified in PKD1^+/- pigs, mirroring ADPKD patient symptoms.
• PKD1 deficiency reduced E-cadherin in airway epithelium, increasing susceptibility to invasion and inflammation.
• Altered extracellular matrix promoted airway smooth muscle cell transition to a proliferative phenotype, leading to airway remodeling and bronchiectasis.

Conclusions:

• The PKD1^+/- pig model effectively recapitulates bronchiectasis pathogenesis in ADPKD.
• PKD1's role in airway epithelium highlights it as a potential therapeutic target for bronchiectasis.
• This research offers insights into novel diagnostic and treatment strategies for ADPKD-related bronchiectasis.