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Am J Physiol Renal Physiol 296: F575-F582, 2009. First published January 7, 2009; doi:10.1152/ajprenal.90705.2008
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Chronic blockade of 20-HETE synthesis reduces polycystic kidney disease in an orthologous rat model of ARPKD

Frank Park,1,2,5 William E. Sweeney, Jr.,3,4,5 Guangfu Jia,1,5 Talha Akbulut,2,5 Benjamin Mueller,5 J. Russell Falck,6 Saritha Birudaraju,6 Richard J. Roman,2,3,5 and Ellis D. Avner2,3,4,5

1Department of Medicine, Division of Nephrology, Departments of 2Physiology, 3Pediatrics, 4Children's Research Institute, and 5Kidney Disease Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and 6Department of Biochemistry, University of Texas-Southwestern, Dallas, Texas

Submitted 24 November 2008 ; accepted in final form 5 January 2009

20-Hydroxyeicosatetraenoic acid (20-HETE) has been implicated as a potential mediator in epithelial cell proliferation and cyst formation in polycystic kidney disease (PKD). In the present study, we studied the effects of chronic blockade of 20-HETE synthesis in an orthologous rodent model of autosomal recessive polycystic kidney disease (ARPKD), the PCK rat. RT-PCR analysis indicated that the expression of CYP4A1, CYP4A2, CYP4A3, and CYP4A8 mRNA was increased two- to fourfold in cystic PCK compared with noncystic Sprague-Dawley rat kidneys. Daily administration of a 20-HETE synthesis inhibitor, HET-0016 (10 mg·kg–1·day–1 ip) for 4–7 wk significantly reduced kidney size by 24% from 4.95 ± 0.19 g in vehicle-treated PCK rats to 3.76 ± 0.15 g (n = 4). Collecting tubule morphometric cystic indices were reduced in HET-0016-treated PCK rats (2.1 ± 0.2; n = 4) compared with vehicle-treated PCK rats (4.4 ± 0.1; n = 4). The cellular mechanism by which 20-HETE may play a role in cyst formation has not been well characterized, but there was a significantly lower (P < 0.05) level of intracellular cAMP and decreased phosphorylation (activation) of ERK1/2 protein in PCK rat kidneys (n = 3) treated with HET-0016 . These studies indicate a potential role of 20-HETE in cyst formation in the orthologous rodent PCK model of ARPKD.

cytochrome P-450; HET-0016; epithelial cell proliferation; polycystic kidney rat; pck; autosomal recessive polycystic kidney mouse


Address for reprint requests and other correspondence: F. Park, Medical College of Wisconsin, 8701 Watertown Plank Rd., HRC 4100, Milwaukee, WI 53226 (e-mail: fpark{at}mcw.edu)




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T. Akbulut, K. R. Regner, R. J. Roman, E. D. Avner, J. R. Falck, and F. Park
20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR- and c-Src-dependent mechanism
Am J Physiol Renal Physiol, September 1, 2009; 297(3): F662 - F670.
[Abstract] [Full Text] [PDF]


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