Inhibition of Cdc25A Suppresses Hepato-Renal Cystogenesis in Rodent Models of Polycystic Kidney and Liver Disease

Abstract

BACKGROUND & AIMS: In polycystic kidney (PKD) and liver (PLD) diseases, the normally non-proliferative hepato-renal epithelia acquire a proliferative, cystic phenotype, which is linked to overexpression of Cdc25A and cell cycle deregulation. We investigated the effects of Cdc25A inhibition in mice and rats, via genetic and pharmacological approaches. METHODS: Cdc25A(+/-) mice (which have reduced levels of Cdc25A) were cross-bred with Pkhd1(del2/del2) mice (which have increased levels of Cdc25A and develop hepatic cysts). Cdc25A expression was analyzed in livers of control and PCK rats, control and 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 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 to 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 PKD and PLD, and might be developed as therapeutics for these diseases.