Methods of modulating cell proliferation and cyst formation in polycystic kidney and liver diseases
The present invention provides a method for preferentially reducing the proliferation of cystic epithelial cells in the kidney or bile duct in a mammal in need thereof by administering a 20-HETE synthesizing enzyme inhibitor or a 20-HETE antagonist to the mammal in an amount sufficient to preferentially reduce the proliferation of cystic epithelial cells over normal epithelial cells such as tubule epithelial cells in the kidney or bile duct. The present invention also provides a method for preventing or treating autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), ARPKD associated congenital hepatic fibrosis, ARPKD associated Caroli's disease, or cholangiocarcinoma in a mammal in need thereof by administering a 20-HETE synthesizing enzyme inhibitor or a 20-HETE antagonist to the mammal in an amount sufficient to prevent or treat the disease.
1. A method for treating a disease in a mammal in need thereof wherein the disease is autosomal dominant polycystic kidney disease (ADPKD), the method comprising the step of administering an agent selected from a 20-HETE synthesizing enzyme inhibitor and a 20-hydroxyeicosatetraenoic acid (20-HETE) antagonist to the mammal in an amount sufficient to treat the disease.
2. The method of claim 1 , wherein the agent is a 20-HETE synthesizing enzyme inhibitor.
3. The method of claim 2 , wherein the 20-HETE synthesizing enzyme inhibitor is a class I hydroxyformamidine compound.
4. The method of claim 2 , wherein the 20-HETE synthesizing enzyme inhibitor is selected from N-hydroxy-N-(4-butyl-2-methylphenyl)-formamidine (HETOO16) and N-(3Chloro-4-morpholin-4-yl)phenyl-N′-hydroxyimidoformamide (TS-011).
5. The method of claim 1 , wherein the mammal is human.
6. The method of claim 1 further comprising the step of observing improvement in the mammal having the disease.
7. The method of claim 2 , wherein the 20-HETE synthesizing enzyme inhibitor is class II hydroxyformamidine compound.
8. The method of claim 2 , wherein the 20-HETE synthesizing enzyme inhibitor is a class Ill hydroxyformamidine compound.
9. The method of claim 2 , wherein the 20-HETE synthesizing enzyme inhibitor is an imidazole derivative 20-HETE synthesis inhibitor.
10. The method of claim 2 , wherein the 20-HETE synthesizing enzyme inhibitor is a pyrazole or isoxazole derivative 20-HETE synthesis inhibitor.