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

Tatyana V. Masyuk, Brynn N. Radtke, Angela J. Stroope, Jesús M. Banales, Anatoliy I. Masyuk, Sergio A. Gradilone, Gabriella Bedekovicsne Gajdos, Natasha Chandok, Jason L. Bakeberg, Christopher J. Ward, Erik L. Ritman, Hiroaki Kiyokawa, Nicholas F La Russo

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27 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)622-633
Number of pages12
JournalGastroenterology
Volume142
Issue number3
DOIs
StatePublished - Mar 2012

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Keywords

  • Animal Model
  • Cell Division
  • Phosphatase
  • Therapeutic Strategy

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Masyuk, T. V., Radtke, B. N., Stroope, A. J., Banales, J. M., Masyuk, A. I., Gradilone, S. A., Gajdos, G. B., Chandok, N., Bakeberg, J. L., Ward, C. J., Ritman, E. L., Kiyokawa, H., & La Russo, N. F. (2012). Inhibition of Cdc25A suppresses hepato-renal cystogenesis in rodent models of polycystic kidney and liver disease. Gastroenterology, 142(3), 622-633. https://doi.org/10.1053/j.gastro.2011.11.036