Inhibition of Cdc25A suppresses hepato-renal cystogenesis in rodent models of polycystic kidney and liver disease

Background & Aims: In polycystic kidney disease and polycystic liver disease (PLD), the normally nonproliferative hepato-renal epithelia acquire a proliferative, cystic phenotype that is linked to overexpression of cell division cycle 25 (Cdc25)A phosphatase and cell-cycle deregulation. We investigated the effects of Cdc25A inhibition in mice and rats via genetic and pharmacologic approaches. Methods: Cdc25A^+/- mice (which have reduced levels of Cdc25A) were cross-bred with polycystic kidney and hepatic disease 1 (Pkhd1^del2/del2) mice (which have increased levels of Cdc25A and develop hepatic cysts). Cdc25A expression was analyzed in livers of control and polycystic kidney (PCK) rats, control and polycystic kidney 2 (Pkd2 ^ws25/-) mice, healthy individuals, and patients with PLD. We examined effects of pharmacologic inhibition of Cdc25A with vitamin K3 (VK3) on the cell cycle, proliferation, and cyst expansion in vitro; hepato-renal cystogenesis in PCK rats and Pkd2^ws25/- mice; and expression of Cdc25A and the cell-cycle proteins regulated by Cdc25A. We also examined the effects of the Cdc25A inhibitor PM-20 on hepato-renal cystogenesis in Pkd2^ws25/- mice. Results: Liver weights and hepatic and fibrotic areas were decreased by 32%52% in Cdc25A^+/-:Pkhd1^del2/del2 mice, compared with Pkhd1^del2/del2 mice. VK3 altered the cell cycle and reduced proliferation of cultured cholangiocytes by 32%83% and decreased growth of cultured cysts by 23%67%. In PCK rats and Pkd2^ws25/- mice, VK3 reduced liver and kidney weights and hepato-renal cystic and fibrotic areas by 18%34%. PM-20 decreased hepato-renal cystogenesis in Pkd2^ws25/- mice by 15%. Conclusions: Cdc25A inhibitors block cell-cycle progression and proliferation, reduce liver and kidney weights and cyst growth in animal models of polycystic kidney disease and PLD, and might be developed as therapeutics for these diseases.