Chronic blockade of 20-HETE synthesis reduces polycystic kidney disease in an orthologous rat model of ARPKD

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