RGD Reference Report - Chronic blockade of 20-HETE synthesis reduces polycystic kidney disease in an orthologous rat model of ARPKD. - Rat Genome Database

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

Authors: Park, F  Sweeney WE, JR  Jia, G  Akbulut, T  Mueller, B  Falck, JR  Birudaraju, S  Roman, RJ  Avner, ED 
Citation: Park F, etal., Am J Physiol Renal Physiol. 2009 Jan 7.
RGD ID: 2303380
Pubmed: PMID:19129252   (View Abstract at PubMed)
PMCID: PMC2660198   (View Article at PubMed Central)
DOI: DOI:10.1152/ajprenal.90705.2008   (Journal Full-text)

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. Reverse transcription-polymerase chain reaction (RT-PCR) analysis indicated that the expression of CYP4A1, CYP4A2, CYP4A3, and CYP4A8 mRNA was increased 2- to 4- fold in cystic PCK compared to non-cystic SD rat kidneys. Daily administration of a 20-HETE synthesis inhibitor, HET-0016 (10 mg/kg/day i.p.) for 4-7 weeks 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 to 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. Key words: autosomal recessive polycystic kidney disease, cytochrome P450, epithelial cell proliferation, 20-HETE, HET-0016.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
autosomal recessive polycystic kidney disease  IEP 2303380; 2303380; 2303380; 2303380mRNA:increased expression:kidneyRGD 
autosomal recessive polycystic kidney disease  ISOCyp4a1 (Rattus norvegicus)2303380mRNA:increased expression:kidneyRGD 
autosomal recessive polycystic kidney disease  ISOCyp4a8 (Rattus norvegicus)2303380mRNA:increased expression:kidneyRGD 
autosomal recessive polycystic kidney disease  ISOCyp4a3 (Rattus norvegicus)2303380mRNA:increased expression:kidneyRGD 

Objects Annotated

Genes (Rattus norvegicus)
Cyp4a1  (cytochrome P450, family 4, subfamily a, polypeptide 1)
Cyp4a2  (cytochrome P450, family 4, subfamily a, polypeptide 2)
Cyp4a3  (cytochrome P450, family 4, subfamily a, polypeptide 3)
Cyp4a8  (cytochrome P450, family 4, subfamily a, polypeptide 8)

Genes (Mus musculus)
Cyp4a10  (cytochrome P450, family 4, subfamily a, polypeptide 10)
Cyp4a12b  (cytochrome P450, family 4, subfamily a, polypeptide 12B)
Cyp4a14  (cytochrome P450, family 4, subfamily a, polypeptide 14)


Additional Information