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

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.

• Authors: 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 LaRusso
• Journal: Gastroenterology (Gastroenterology) Vol. 142 Issue 3 Pg. 622-633.e4 (Mar 2012) ISSN: 1528-0012 [Electronic] United States
• PMID: 22155366 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Pkhd1 protein, mouse
• Receptors, Cell Surface
• TRPP Cation Channels
• polycystic kidney disease 2 protein
• Vitamin K 3
• CDC25A protein, human
• Cdc25a protein, mouse
• Cdc25a protein, rat
• cdc25 Phosphatases

Topics

• Animals
• Bile Ducts, Intrahepatic (drug effects, enzymology, pathology)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Cysts (drug therapy, enzymology, genetics, pathology)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Humans
• Kidney (drug effects, enzymology, pathology)
• Liver (drug effects, enzymology, pathology)
• Liver Diseases (drug therapy, enzymology, genetics, pathology)
• Mice
• Mice, Knockout
• Organ Size (drug effects)
• Polycystic Kidney, Autosomal Recessive (drug therapy, enzymology, genetics, pathology)
• Rats
• Receptors, Cell Surface (genetics, metabolism)
• TRPP Cation Channels (genetics, metabolism)
• Time Factors
• Up-Regulation
• Vitamin K 3 (pharmacology)
• cdc25 Phosphatases (antagonists & inhibitors, deficiency, genetics, metabolism)