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 selected from autosomal recessive polycystic kidney disease (ARPKD), ARPKD associated congenital hepatic fibrosis, and ARPKD associated Caroli's disease, the method comprising the step of:
administering an agent selected from a 20-hydroxyeicosatetraenoic acid (20-HETE) synthesizing enzyme inhibitor and a 20-HETE antagonist to the mammal in an amount sufficient to prevent or treat the disease.
2. The method of claim 1 , wherein the disease is ARPKD.
3. The method of claim 1 , wherein the mammal is human.
4. The method of claim 1 further comprising the step of:
observing improvement in the mammal having the disease.
5. The method of claim 1 , wherein the agent is a 20-HETE synthesizing enzyme inhibitor.
6. The method of claim 5 , wherein the 20-HETE synthesizing enzyme inhibitor is selected from N-hydroxy-N′-(4-n-butyl-2-methylphenyl)-formamidine (HET0016) and N-(3-Chloro-4-morpholin-4-yl)phenyl-N′-hydroxyimidoformamide (TS-011).
7. The method of claim 5 , wherein the 20-HETE synthesizing enzyme inhibitor is selected from a class I hydroxyformamidine compound 20-HETE synthesis inhibitor.
8. The method of claim 5 , wherein the 20-HETE synthesizing enzyme inhibitor is selected from a class II hydroxyformamidine compound 20-HETE synthesis inhibitor.
9. The method of claim 5 , wherein the 20-HETE synthesizing enzyme inhibitor is selected from a class III hydroxyformamidine compound 20-HETE synthesis inhibitor.
10. The method of claim 5 , wherein the 20-HETE synthesizing enzyme inhibitor is selected from an imidazole derivative 20-HETE synthesis inhibitor.
11. The method of claim 5 , wherein the 20-HETE synthesizing enzyme inhibitor is selected from a pyrazole derivative 20-HETE synthesis inhibitor.
12. The method of claim 5 , wherein the 20-HETE synthesizing enzyme inhibitor is selected from an isoxazole derivative 20-HETE synthesis inhibitor.
13. The method of claim 1 , wherein the agent is a 20-HETE antagonist.