Several cellular processes and pathways were altered both by fluid shear stress and Pkd1 gene disruption in renal epithelial cells. Many of these signaling pathways are implicated in ADPKD as... Show moreSeveral cellular processes and pathways were altered both by fluid shear stress and Pkd1 gene disruption in renal epithelial cells. Many of these signaling pathways are implicated in ADPKD as well. However, more than 20 years after the discovery of PKD1 and PKD2 as genetic cause of ADPKD, the exact cellular function of the polycystins still remains unclear. Our data indicate that polycystin-1 is not a direct mechano-sensor, but it restrains shear stress induced gene expression via an unknown mechanism. Additional research is required to identify the cellular function of polycystins and the mechanism of mechanotransduction. This is needed to refine the mechanism of cyst formation in ADPKD and other ciliopathies, which could identify potential targets for therapy. Nevertheless, we showed that inhibition of activin signaling is a promising therapy to slow cyst progression in Pkd1del mice. Although other treatment strategies have been tested successfully to reduce PKD progression in pre-clinical studies, the efficacy in human patients is sometimes minimal or absent. Therefore, it has been suggested to target multiple signaling pathways affected in ADPKD. These combined therapies should reestablish the balance in cellular signaling of renal epithelial cells and maintain cellular homeostasis within physiological boundaries. Show less
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... Show moreAutosomal 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. Show less