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 R Falck, Saritha Birudaraju, Richard J. Roman, Ellis D. Avner

Research output: Contribution to journalArticle

18 Citations (Scopus)

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 - Mar 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

Keywords

  • Autosomal recessive polycystic kidney mouse
  • Cytochrome P-450
  • Epithelial cell proliferation
  • HET-0016
  • Pck
  • Polycystic kidney rat

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

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 R; Birudaraju, Saritha; Roman, Richard J.; Avner, Ellis D.

In: American Journal of Physiology - Renal Physiology, Vol. 296, No. 3, 03.2009.

Research output: Contribution to journalArticle

Park, Frank ; Sweeney, William E. ; Jia, Guangfu ; Akbulut, Talha ; Mueller, Benjamin ; Falck, J R ; 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 - Sweeney, William E.

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AU - Akbulut, Talha

AU - Mueller, Benjamin

AU - Falck, J R

AU - Birudaraju, Saritha

AU - Roman, Richard J.

AU - Avner, Ellis D.

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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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