20-HETE mediates proliferation of renal epithelial cells in polycystic kidney disease.
Polycystic kidney diseases are characterized by abnormal proliferation of renal epithelial cells. In this study, the role of 20-hydroxyeicosatetraenoic acid (20-HETE), an endogenous cytochrome P450 metabolite of arachidonic acid with mitogenic properties, was evaluated in cystic renal disease. Daily administration of HET-0016, an inhibitor of 20-HETE synthesis, significantly reduced kidney size by half in the BPK mouse model of autosomal recessive polycystic kidney disease. In addition, compared with untreated BPK mice, this treatment significantly reduced collecting tubule cystic indices and approximately doubled survival. For evaluation of the role of 20-HETE as a mediator of epithelial cell proliferation, principal cells isolated from cystic BPK and noncystic Balb/c mice were genetically modified using lentiviral vectors. Noncystic Balb/c cells overproducing Cyp4a12 exhibited a four- to five-fold increase in cell proliferation compared with control Balb/c cells, and this increase was completely abolished when 20-HETE synthesis was inhibited; therefore, this study suggests that 20-HETE mediates proliferation of epithelial cells in the formation of renal cysts.
Park
Frank
F
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA. fpark@mcw.edu
Sweeney
William E
WE
Jia
Guangfu
G
Roman
Richard J
RJ
Avner
Ellis D
ED
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism / Q000502:physiology; D000072470:Cytochrome P450 Family 4; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000502:physiology*; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D007690:Polycystic Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*
D000578:Amidines; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; C493210:Cyp4a12a protein, mouse; D000072470:Cytochrome P450 Family 4