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Published ahead of print on July 2, 2008
J Am Soc Nephrol 19: 1929-1939, 2008
© 2008 American Society of Nephrology
doi: 10.1681/ASN.2007070771
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BASIC RESEARCH

20-HETE Mediates Proliferation of Renal Epithelial Cells in Polycystic Kidney Disease

Frank Park*,{dagger},{ddagger}, William E. Sweeney{ddagger},§,||, Guangfu Jia*,{ddagger}, Richard J. Roman{dagger},{ddagger},§ and Ellis D. Avner{dagger},{ddagger},§,||

* Department of Medicine, Division of Nephrology, {dagger} Department of Physiology, § Department of Pediatrics, and || Children's Research Institute, {ddagger} Kidney Disease Center, Medical College of Wisconsin, Milwaukee, Wisconsin

Correspondence: Dr. Frank Park, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Road, HRC 4100, Milwaukee, WI 53226. Phone: 414-456-8130; Fax: 414-456-6312; E-mail: fpark{at}mcw.edu

Received for publication July 16, 2007. Accepted for publication April 23, 2008.

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.






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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673