期刊
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
卷 296, 期 3, 页码 F575-F582出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.90705.2008
关键词
cytochrome P-450; HET-0016; epithelial cell proliferation; polycystic kidney rat; pck; autosomal recessive polycystic kidney mouse
资金
- Polycystic Kidney Disease (PKD) Foundation
- National Institutes of Health [HL-36279, P50-DK057306, GM-31278]
- Robert A. Welch Foundation
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL036279, R37HL036279] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P50DK057306, P50DK079306] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM031278] Funding Source: NIH RePORTER
Park F, Sweeney WE Jr, Jia G, Akbulut T, Mueller B, Falck JR, Birudaraju S, Roman RJ, Avner ED. Chronic blockade of 20-HETE synthesis reduces polycystic kidney disease in an orthologous rat model of ARPKD. Am J Physiol Renal Physiol 296: F575-F582, 2009. First published January 7, 2009; doi:10.1152/ajprenal.90705.2008.-20-Hydroxycicosatetracnoic 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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