VEGF receptor inhibition blocks liver cyst growth in pkd2(WS25/-) mice

Proliferation of cyst-lining epithelial cells is an integral part of autosomal dominant polycystic kidney disease ( ADPKD) cyst growth. Cytokines and growth factors within cyst fluids are positioned to induce cyst growth. Vascular endothelial growth factor ( VEGF) is a pleiotropic growth factor present in ADPKD liver cyst fluids ( human 1,128 +/- 78, mouse 2,787 +/- 136 pg/ml) and, to a lesser extent, in ADPKD renal cyst fluids ( human 294 +/- 41, mouse 191 +/- 90 pg/ml). Western blotting showed that receptors for VEGF (VEGFR1 and VEGFR2) were present in both normal mouse bile ducts and pkd2(WS25/-) liver cyst epithelial cells. Treatment of pkd2(WS25/-) liver cyst epithelial cells with VEGF (50-50,000 pg/ml) or liver cyst fluid induced a proliferative response. The effect on proliferation of liver cyst fluid was inhibited by SU-5416, a potent VEGF receptor inhibitor. Treatment of pkd2(WS25/-) mice between 4 and 8 mo of age with SU-5416 markedly reduced the cyst volume density of the liver ( vehicle 9.9 +/- 4.3%, SU-5416 1.8 +/- 0.7% of liver). SU-5416 treatment between 4 and 12 mo of age markedly protected against increases in liver weight [ pkd2(+/ +) 4.8 +/- 0.2%, pkd2(WS25/-)- vehicle 10.8 +/- 1.9%, pkd2( WS25/-)-SU-5416 4.8 +/- 0.4% body wt]. The capacity of VEGF signaling to induce in vitro proliferation of pkd2( WS25/-) liver cyst epithelial cells and inhibition of in vivo VEGF signaling to retard liver cyst growth in pkd2( WS25/-) mice indicates that the VEGF signaling pathway is a potentially important therapeutic target in the treatment of ADPKD liver cyst disease.