title: Inhibition of Cdc25A suppresses hepato-renal cystogenesis in rodent models of polycystic kidney and liver disease.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Masyuk
authors.forename: Brynn N
authors.initials: BN
authors.lastname: Radtke
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Stroope
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Banales
authors.forename: Anatoliy I
authors.initials: AI
authors.lastname: Masyuk
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Gradilone
authors.forename: Gabriella Bedekovicsne
authors.initials: GB
authors.lastname: Gajdos
authors.forename: Natasha
authors.initials: N
authors.lastname: Chandok
authors.forename: Jason L
authors.initials: JL
authors.lastname: Bakeberg
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Ward
authors.forename: Erik L
authors.initials: EL
authors.lastname: Ritman
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kiyokawa
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: LaRusso
mesh_terms: D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003560:Cysts / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D017044:Polycystic Kidney, Autosomal Recessive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D024483:Vitamin K 3 / Q000494:pharmacology*; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011956:Receptors, Cell Surface; D050396:TRPP Cation Channels; D024483:Vitamin K 3; D020687:cdc25 Phosphatases; C484365:Pkhd1 protein, mouse; C517004:CDC25A protein, human; C517005:Cdc25a protein, mouse; C517007:Cdc25a protein, rat