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Renal Cyclooxygenase Products are Higher and Lipoxygenase Products are Lower in Early Disease in the pcy Mouse Model of Adolescent Nephronophthisis

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Lipids

Abstract

Nephronophthisis (NPHP) is a pediatric form of hereditary polycystic kidney disease (PKD), and is the leading cause of end stage renal disease in children. The pcy mouse is an orthologous model of human NPHP, with a mutation in the Nphp3 gene. Renal phospholipase A2, cyclooxygenase (COX) 1 and cyclic AMP are elevated in this model, suggesting that eicosanoid formation may be altered. In another type of PKD observed in the Han:SPRD-Cy rat, inhibition of eicosanoid production slows disease progression. If renal eicosanoids are similarly altered in NPHP, potential for pharmacologic intervention also may exist for this disorder. Therefore, renal fatty acids and eicosanoids were determined in pcy and normal mice at 15, 30 and 60 days of age by gas chromatography and HPLC–tandem mass spectrometry, respectively. Renal cysts in enlarged kidneys were observed in pcy mice by 15 days of age and increased over time. Renal phospholipid ARA levels were higher in pcy compared to normal mice at 15 and 30 days. Eicosanoid differences were observed starting at 30 days, when the COX products 6-keto-prostaglandin (PG) F1α, thromboxane B2 and PGE2 were higher in pcy compared to normal kidneys. Overall, total COX products were elevated at 30 and 60 days. In contrast, the levels of the lipoxygenase (LOX) products were not altered until 60 days of age and these were lower in pcy kidneys compared to normal. These findings suggest that altered eicosanoids play a role in NPHP, and that manipulating these levels with pharmacologic agents may have therapeutic potential.

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Abbreviations

COX:

Cyclooxygenase

HETE:

Hydroxyeicosatetraenoic acid

HODE:

Hydroxyoctadecadienoic acid

LOX:

Lipoxygenase

NPHP:

Nephronophthisis

PG:

Prostaglandin

PKD:

Polycystic kidney disease

TX:

Thromboxane

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Acknowledgments

This study was funded by a grant (to HMA) from the Natural Sciences and Engineering Research Council of Canada (312062) and by a Grant-in-Aid for scientific research (22590351) to SN from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. The Manitoba Institute of Child Health provided studentships to CL and AR.

Conflict of interest

The authors declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Department of Human Nutritional Sciences, University of Manitoba, W573 Duff Roblin Building, Winnipeg, MB, R3T 2N2, Canada

    Tamio Yamaguchi, Clara Lysecki, Ashleigh Reid & Harold M. Aukema

  2. Canadian Centre for Agri-Food Research in Health and Medicine, Winnipeg, MB, R2H 2A6, Canada

    Tamio Yamaguchi, Clara Lysecki, Ashleigh Reid & Harold M. Aukema

  3. Education and Research Center of Animal Models for Human Diseases, Fujita Health University, Toyoake, Aichi, 470-1192, Japan

    Shizuko Nagao

  4. Manitoba Institute of Child Health, Winnipeg, MB, R3E 3P4, Canada

    Clara Lysecki, Ashleigh Reid & Harold M. Aukema

Authors
  1. Tamio Yamaguchi
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  2. Clara Lysecki
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  3. Ashleigh Reid
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  4. Shizuko Nagao
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  5. Harold M. Aukema
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Corresponding author

Correspondence to Harold M. Aukema.

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Supplementary material 1 (DOCX 27 kb)

Supplementary Fig. 1 Sum of (a) COX and (b) LOX products in normal (CD1-+/+) and pcy (CD1-pcy/pcy) mice. **P < 0.01, ***P < 0.001: Significantly different from corresponding value for mice at same age. Different upper case letters indicate significant age differences (P < 0.05). Values are expressed as means ± SE, n = 6

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Yamaguchi, T., Lysecki, C., Reid, A. et al. Renal Cyclooxygenase Products are Higher and Lipoxygenase Products are Lower in Early Disease in the pcy Mouse Model of Adolescent Nephronophthisis. Lipids 49, 39–47 (2014). https://doi.org/10.1007/s11745-013-3859-2

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  • DOI: https://doi.org/10.1007/s11745-013-3859-2

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