Cyst initiation, cyst expansion and progression in ADPKD

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by large fluid-filled cysts and progressive deterioration of renal function necessitating renal replacement therapy. In this thesis different phases of ADPKD were studied. First, we studied the initiation of cyst formation. We showed that the proliferative status of the renal tissue is important for the rate at which cysts are formed after Pkd1 conditional deletion. In addition we concluded that improper positioning of centrosomes and altered canonical Wnt signaling are early events after Pkd1-gene disruption. Subsequently, we provided evidence for altered activation of the Hippo signaling pathway in cyst growth in ADPKD, suggesting that aberrant Hippo signaling is not an initiating event in cyst formation but accompanies progressive cystic growth. The Hippo-pathway provides a novel target for inhibiting cyst expansion PKD. Finally, we studied ADPKD disease progression and showed that cyst expansion is followed regression of cystic and renal volume accompanied by fibrosis and inflammation. Our data suggest suggests that renal volume may not be the best predictor of progression to renal failure and end stage renal disease. Cyst growth and ADPKD disease progression are complex processes regulated by many signaling networks. This not only provides many targets for therapeutic intervention but is also a difficulty at the same time. Aiming for a single therapeutic target will most likely be not successful, and therapeutic intervention in ADPKD requires a multi-target therapy.