Chronic blockade of 20-HETE synthesis reduces polycystic kidney disease in an orthologous rat model of ARPKD.
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 x kg(-1) x 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.
Park
Frank
F
Department of Medicine, Division of Nephrology, Medical College of Wisconsin, 8701 Watertown Plank Rd., HRC 4100, Milwaukee, Wisconsin 53226, USA. fpark@mcw.edu
Sweeney
William E
WE
Jia
Guangfu
G
Akbulut
Talha
T
Mueller
Benjamin
B
Falck
J Russell
JR
Birudaraju
Saritha
S
Roman
Richard J
RJ
Avner
Ellis D
ED
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004852:Epoxy Compounds / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D007668:Kidney / Q000473:pathology*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D009929:Organ Size; D017044:Polycystic Kidney, Autosomal Recessive / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000578:Amidines; D004852:Epoxy Compounds; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; D020033:Protein Isoforms; D012333:RNA, Messenger; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D000242:Cyclic AMP; D042926:Cytochrome P-450 CYP4A; D048049:Extracellular Signal-Regulated MAP Kinases; D015126:8,11,14-Eicosatrienoic Acid