Faculty Collaboration Database

Chronic blockade of 20-HETE synthesis reduces polycystic kidney disease in an orthologous rat model of ARPKD. Am J Physiol Renal Physiol 2009 Mar;296(3):F575-82

Date

01/09/2009

Pubmed ID

19129252

Pubmed Central ID

PMC2660198

DOI

10.1152/ajprenal.90705.2008

Scopus ID

2-s2.0-66049111009 (requires institutional sign-in at Scopus site)   22 Citations

Abstract

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.

Author List

Park F, Sweeney WE Jr, Jia G, Akbulut T, Mueller B, Falck JR, Birudaraju S, Roman RJ, Avner ED

Author

Ellis D. Avner MD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

8,11,14-Eicosatrienoic Acid
Amidines
Animals
Cyclic AMP
Cytochrome P-450 CYP4A
Disease Models, Animal
Enzyme Activation
Epoxy Compounds
Extracellular Signal-Regulated MAP Kinases
Hydroxyeicosatetraenoic Acids
Kidney
Male
Microsomes
Organ Size
Polycystic Kidney, Autosomal Recessive
Protein Isoforms
RNA, Messenger
Rats
Rats, Sprague-Dawley