Aims Although effective in preventing tumour growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin (ET)-1 up... Show moreAims Although effective in preventing tumour growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin (ET)-1 up-regulation. ET-1 via stimulation of the ETA receptor has pro-hypertensive actions whereas stimulation of the ETB receptor can elicit both pro- or antihypertensive effects. In this study, our aim was to determine the efficacy of selective ETA vs. dual ETA/B receptor blockade for the prevention of angiogenesis inhibitor-induced hypertension and albuminuria.Methods and results Male Wistar Kyoto (WKY) rats were treated with vehicle, sunitinib (angiogenesis inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ETA/B receptor antagonist; 30 mg/kg/day) or sitaxentan (selective ETA receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Compared with vehicle, sunitinib treatment caused a rapid and sustained increase in mean arterial pressure of similar to 25 mmHg. Co-treatment with macitentan or sitaxentan abolished the pressor response to sunitinib. Sunitinib did not induce endothelial dysfunction. However, it was associated with increased aortic, mesenteric, and renal oxidative stress, an effect that was absent in mesenteric arteries of the macitentan and sitaxentan co-treated groups. Albuminuria was greater in the sunitinib- than vehicle-treated group. Co-treatment with sitaxentan, but not macitentan, prevented this increase in albuminuria. Sunitinib treatment increased circulating and urinary prostacyclin levels and had no effect on thromboxane levels. These increases in prostacyclin were blunted by co-treatment with sitaxentan.Conclusions Our results demonstrate that both selective ETA and dual ETA/B receptor antagonism prevents sunitinib-induced hypertension, whereas sunitinib-induced albuminuria was only prevented by selective ETA receptor antagonism. In addition, our results uncover a role for prostacyclin in the development of these effects. In conclusion, selective ETA receptor antagonism is sufficient for the prevention of sunitinib-induced hypertension and renal injury. 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
Our kidneys play a major role in regulating the body__s internal environment, via transportation of water, salt, potassium and waste products. As a result of this transport function, cells within... Show moreOur kidneys play a major role in regulating the body__s internal environment, via transportation of water, salt, potassium and waste products. As a result of this transport function, cells within the kidney are relatively sensitive to injury. This injury can occur when the kidneys are exposed to anticancer drugs, antibiotics, toxic chemicals or as a result of a drop in blood flow during kidney transplantation (ischemia/reperfusion injury). As a consequence, renal function is rapidly lost. The primary targets for injury are epithelial cells lining the proximal tubule. These cells rest on a basement membrane via cell-matrix interactions and are connected to each other via cell-cell interactions. At these adhesion sites, several signalling complexes are located, which are linked to the F-actin cytoskeleton of the cell. When cells are damaged, they alter or may loose their cell-cell and cell-matrix adhesions in association with reorganization of the actin cytoskeleton. This is associated with changes in the activation status of several signal transduction pathways. The research described in this thesis was designed to identify __new__ signalling pathways involved in renal cell injury and understand their role in this process. The changes in protein expression and phosphorylation that occur in association with changes in cell adhesion and cytoskeletal organization prior to or during renal cell injury were analyzed using 2D-Difference In Gel Electrophoresis (DIGE) and 2D-phosphotyrosine blotting.the protein identifications that are described in this thesis point to a more common observation of alterations in the F-actin cytoskeleton that take place during the process of renal cell injury and regeneration. Assessing the precise role of these proteins and their phosphorylation status will increase our understanding of the events that take place during this process. Show less
