Abstract: TH-PO578

Altered Liver Bioactive Lipid (Oxylipin) Profiles in PCK Rats with Polycystic Kidney and Liver Disease

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases

Authors

  • Yamaguchi, Tamio, Department of Clinical Nutrition, Suzuka University of Medical Science, Suzuka, Mie, Japan
  • Devassy, Jessay Gopuran, University of Manitoba, Winnipeg, Manitoba, Canada
  • Jha, Aruni, University of Manitoba, Winnipeg, Manitoba, Canada
  • Halayko, Andrew J, University of Manitoba, Winnipeg, Manitoba, Canada
  • Kugita, Masanori, Fujita Health University, Toyoake, Aichi, Japan
  • Nagao, Shizuko, Fujita Health University, Toyoake, Aichi, Japan
  • Ravandi, Amir, St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada
  • Aukema, Harold M., University of Manitoba, Winnipeg, Manitoba, Canada
Background

Oxylipins are bioactive lipids derived from polyunsaturated fatty acids formed via cyclooxygenase (COX), cytochrome P450 (CYP) and lipoxygenase activities. Previously, we reported that renal COX oxylipins were elevated in diverse animal models of renal cystic kidney disease, suggesting that COX inhibition may be a viable approach to treating these types of renal disorders. Since liver cystic disease also commonly occurs in several types of renal cystic disease, we determined kidney and liver oxylipin profiles in the PCK rat, an orthologous model of autosomal recessive polycystic kidney disease (ARPKD) with cystic kidney and liver disease.

Methods

Liver oxylipin profiles of 16-week PCK and normal rats were determined by targeted lipidomic analyses using HPLC-tandem mass spectrometry. Correlations of oxylipins with disease were analyzed using supervised and unsupervised multivariate models.

Results

Both kidney and liver weight/body weight and lumen or cyst area/tissue section, as well as liver fibrosis were higher in PCK compared to normal rats. Based on the profile of the 61 oxylipins detected in liver, diseased rats clustered distinctly from normals. Consistent with previous findings in which higher levels of renal oxylipins derived via the COX pathway were associated with disease, the strongest predictor of diseased liver was elevated COX derived 6-keto-prostaglandin F, the main metabolite of prostacyclin. In addition, all 7 of the dihydroxy fatty acid oxylipins formed via CYP and soluble epoxide hydrolase (sEH) that were detected were reduced in diseased livers, also consistent with kidney findings. The unsupervised multivariate model also indicated the correlation of diseased livers with at least 9 lipoxygenase derived oxylipins.

Conclusion

Oxylipins from all three biosynthetic pathways are associated with diseased livers in the PCK rat model of ARPKD. The COX derived oxylipin 6-keto-prostaglandin F is higher and CYP/sEH derived oxylipins are lower in PCK livers compared to normals. The potential effects of prostacyclin synthase inhibitors and the role of the novel CYP/sEH derived oxylipins in the development of cystic kidneys and livers remains to be elucidated.

Funding

  • Government Support - Non-U.S.