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

Frank Park, William E. Sweeney, Guangfu Jia, Talha Akbulut, Benjamin Mueller, J. Russell Falck, Saritha Birudaraju, Richard J. Roman, Ellis D. Avner

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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·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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume296
Issue number3
DOIs
StatePublished - Jan 1 2009

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Autosomal Recessive Polycystic Kidney
Polycystic Kidney Diseases
Cysts
Kidney
Rodentia
Sprague Dawley Rats
Epithelial Cells
Phosphorylation
Cell Proliferation
20-hydroxy-5,8,11,14-eicosatetraenoic acid
Polymerase Chain Reaction
Messenger RNA
N-hydroxy-N'-(4-butyl-2-methylphenyl)formamidine
Proteins

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology

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Chronic blockade of 20-HETE synthesis reduces polycystic kidney disease in an orthologous rat model of ARPKD. / Park, Frank; Sweeney, William E.; Jia, Guangfu; Akbulut, Talha; Mueller, Benjamin; Falck, J. Russell; Birudaraju, Saritha; Roman, Richard J.; Avner, Ellis D.

In: American Journal of Physiology - Renal Physiology, Vol. 296, No. 3, 01.01.2009.

Research output: Contribution to journalArticle

Park, Frank ; Sweeney, William E. ; Jia, Guangfu ; Akbulut, Talha ; Mueller, Benjamin ; Falck, J. Russell ; Birudaraju, Saritha ; Roman, Richard J. ; Avner, Ellis D. / Chronic blockade of 20-HETE synthesis reduces polycystic kidney disease in an orthologous rat model of ARPKD. In: American Journal of Physiology - Renal Physiology. 2009 ; Vol. 296, No. 3.
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AU - Mueller, Benjamin

AU - Falck, J. Russell

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AU - Roman, Richard J.

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AB - 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.

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