S. Saadi-kheddouci et al., Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene, ONCOGENE, 20(42), 2001, pp. 5972-5981
Autosomal dominant polycystic kidney disease (ADPKD) is common and is a maj
or cause of renal failure. Although the genetics of ADPKD are well known an
d have led to the discovery of polycystins, a new protein family, the patho
genesis of the disease remains largely unknown. Recent studies have indicat
ed that the beta -catenin signaling pathway is one of the targets of the tr
ansduction pathway controlled by the polycystins. We have generated transge
nic mice that overproduce an oncogenic form of beta -catenin in the epithel
ial cells of the kidney. These mice developed severe polycystic lesions soo
n after birth that affected the glomeruli, proximal, distal tubules and col
lecting ducts. The phenotype of these mice mimicked the human ADPKD phenoty
pe. Cyst formation was associated with an increase in cell proliferation an
d apoptosis. The cell proliferation and apoptotic indexes was increased 4-5
-fold and 3-4-fold, respectively, in cystic tubules of the transgenic mice
compared to that of littermate controls. Our findings provide experimental
genetic evidence that activation of the Wnt/beta -catenin signaling pathway
causes polycystic kidney disease and support the view that dysregulation o
f the Wnt/beta -catenin signaling is involved in its pathogenesis.