Skip to main content
SpringerLink
Log in

Serum oxylipin profiles in IgA nephropathy patients reflect kidney functional alterations

  • Original Article
  • Published:
Metabolomics Aims and scope Submit manuscript

Abstract

Immunoglobulin A nephropathy (IgAN) is a leading cause of chronic kidney disease, frequently associated with hypertension and renal inflammation. ω-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fish oil (FO) improve kidney function in animal models, but have inconsistent metabolic effects in humans. Oxylipin profiles in serum from IgAN patients supplemented with either FO or corn oil (CO) placebo were analyzed by liquid chromatography coupled to tandem mass spectrometry. EPA cyclooxygenase and lipoxygenase metabolites, and EPA and DHA epoxides and diols were increased in response to FO supplementation, as were total epoxides and epoxide/diol ratios. Several of these metabolites were drivers of separation as assessed by multivariate analysis of FO patients pre- versus post-supplementation, including 17,18-dihydroxyeicosatrienoic acid, prostaglandin D3, prostagalandin E3, Resolvin E1, 12-hydroxyeicosapentaenoic acid, and 10(11)-epoxydocosapentaenoic acid. In patients whose proteinuria improved, plasma total oxylipins as well as several hydroxyoctadecadienoic acids, hydroxyeicosatetraenoic acids, and leukotriene B4 metabolites were among the metabolites that were significantly lower than in patients whose proteinuria either did not improve or worsened. These data support the involvement of oxylipins in the inflammatory component of IgAN as well as the potential use of oxylipin profiles as biomarkers and for assessing responsiveness to ω-3 fatty acid supplementation in IgAN patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Alexopoulos, E., Stangou, M., Pantzaki, A., Kirmizis, D., & Memmos, D. (2004). Treatment of severe IgA nephropathy with omega-3 fatty acids: The effect of a “very low dose” regimen. Renal Failure, 26(4), 453–459.

    Article  PubMed  CAS  Google Scholar 

  • Appel, G. B., & Waldman, M. (2006). The IgA nephropathy treatment dilemma. Kidney International, 69(11), 1939–1944.

    Article  PubMed  CAS  Google Scholar 

  • Baratelli, F., Krysan, K., Heuze-Vourc’h, N., Zhu, L., Escuadro, B., Sharma, S., et al. (2005a). PGE2 confers survivin-dependent apoptosis resistance in human monocyte-derived dendritic cells. Journal of Leukocyte Biology, 78(2), 555–564. doi:10.1189/jlb.1004569.

    Article  PubMed  CAS  Google Scholar 

  • Baratelli, F., Lin, Y., Zhu, L., Yang, S. C., Heuze-Vourc’h, N., Zeng, G., et al. (2005b). Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+T cells. Journal of Immunology, 175(3), 1483–1490.

    CAS  Google Scholar 

  • Baxter, G. M. (1995). Alterations of endothelium-dependent digital vascular responses in horses given low-dose endotoxin. Veterinary Surgery, 24(2), 87–96.

    Article  PubMed  CAS  Google Scholar 

  • Bennett, W. M., Walker, R. G., & Kincaid-Smith, P. (1989). Treatment of IgA nephropathy with eicosapentanoic acid (EPA): A two-year prospective trial. Clinical Nephrology, 31(3), 128–131.

    PubMed  CAS  Google Scholar 

  • Branten, A. J., Klasen, I. S., & Wetzels, J. F. (2002). Short-term effects of fish oil treatment on urinary excretion of high- and low-molecular weight proteins in patients with IgA nephropathy. Clinical Nephrology, 58(4), 267–274.

    PubMed  CAS  Google Scholar 

  • Catella-Lawson, F. (2001). Vascular biology of thrombosis: Platelet-vessel wall interactions and aspirin effects. Neurology, 57(5 Suppl 2), S5–S7.

    Article  PubMed  CAS  Google Scholar 

  • Chang, J. H., Kim, D. K., Kim, H. W., Park, S. Y., Yoo, T. H., Kim, B. S., et al. (2009). Changing prevalence of glomerular diseases in Korean adults: A review of 20 years of experience. Nephrology, Dialysis, Transplantation, 24(8), 2406–2410. doi:10.1093/ndt/gfp091.

    Article  PubMed  Google Scholar 

  • Cheng, I. K., Chan, P. C., & Chan, M. K. (1990). The effect of fish-oil dietary supplement on the progression of mesangial IgA glomerulonephritis. Nephrology, Dialysis, Transplantation, 5(4), 241–246.

    PubMed  CAS  Google Scholar 

  • Clevers, H. (2006). Colon cancer–understanding how NSAIDs work. New England Journal of Medicine, 354(7), 761–763. doi:10.1056/NEJMcibr055457.

    Article  PubMed  CAS  Google Scholar 

  • Donadio, J. V., & Grande, J. P. (2004). The role of fish oil/omega-3 fatty acids in the treatment of IgA nephropathy. Seminars in Nephrology, 24(3), 225–243.

    Article  PubMed  CAS  Google Scholar 

  • Donadio, J. V., Bergstralh, E. J., Offord, K. P., Holley, K. E., & Spencer, D. C. (1994a). Clinical and histopathologic associations with impaired renal function in IgA nephropathy. Mayo Nephrology Collaborative Group. Clinical Nephrology, 41(2), 65–71.

    PubMed  CAS  Google Scholar 

  • Donadio, J. V, Jr, Bergstralh, E. J., Offord, K. P., Spencer, D. C., & Holley, K. E. (1994b). A controlled trial of fish oil in IgA nephropathy. Mayo Nephrology Collaborative Group. New England Journal of Medicine, 331(18), 1194–1199.

    Article  PubMed  Google Scholar 

  • Donadio, J. V, Jr, Grande, J. P., Bergstralh, E. J., Dart, R. A., Larson, T. S., & Spencer, D. C. (1999). The long-term outcome of patients with IgA nephropathy treated with fish oil in a controlled trial. Mayo Nephrology Collaborative Group. Journal of the American Society of Nephrology, 10(8), 1772–1777.

    PubMed  CAS  Google Scholar 

  • Donadio, J. V, Jr, Larson, T. S., Bergstralh, E. J., & Grande, J. P. (2001). A randomized trial of high-dose compared with low-dose omega-3 fatty acids in severe IgA nephropathy. Journal of the American Society of Nephrology, 12(4), 791–799.

    PubMed  CAS  Google Scholar 

  • Funk, C. D. (2001). Prostaglandins and leukotrienes: Advances in eicosanoid biology. Science, 294(5548), 1871–1875.

    Article  PubMed  CAS  Google Scholar 

  • Harmon, S. D., Fang, X., Kaduce, T. L., Hu, S., Raj Gopal, V., Falck, J. R., et al. (2006). Oxygenation of [omega]-3 fatty acids by human cytochrome P450 4F3B: Effect on 20-hydroxyeicosatetraenoic acid production. Prostaglandins Leukotrienes and Essential Fatty Acids, 75(3), 169–177.

    Article  CAS  Google Scholar 

  • Hogg, R. J. (1995). A randomized, placebo-controlled, multicenter trial evaluating alternate-day prednisone and fish oil supplements in young patients with immunoglobulin A nephropathy. Scientific Planning Committee of the IgA Nephropathy Study. American Journal of Kidney Diseases, 26(5), 792–796.

    Article  PubMed  CAS  Google Scholar 

  • Hogg, R. J., Lee, J., Nardelli, N., Julian, B. A., Cattran, D., Waldo, B., et al. (2006). Clinical trial to evaluate omega-3 fatty acids and alternate day prednisone in patients with IgA nephropathy: Report from the Southwest Pediatric Nephrology Study Group. Clinical Journal of the American Society of Nephrology, 1(3), 467–474. doi:10.2215/CJN.01020905.

    Article  PubMed  CAS  Google Scholar 

  • Holman, R. T., Johnson, S. B., Bibus, D., Spencer, D. C., & Donadio, J. V, Jr. (1994). Essential fatty acid deficiency profiles in idiopathic immunoglobulin A nephropathy. American Journal of Kidney Diseases, 23(5), 648–654.

    PubMed  CAS  Google Scholar 

  • Imig, J. D., Zhao, X., Zaharis, C. Z., Olearczyk, J. J., Pollock, D. M., Newman, J. W., et al. (2005). An orally active epoxide hydrolase inhibitor lowers blood pressure and provides renal protection in salt-sensitive hypertension. Hypertension, 46(4), 975–981. doi:10.1161/01.HYP.0000176237.74820.75.

    Article  PubMed  CAS  Google Scholar 

  • Jira, W., Spiteller, G., & Richter, A. (1997). Increased levels of lipid oxidation products in low density lipoproteins of patients suffering from rheumatoid arthritis. Chemistry and Physics of Lipids, 87(1), 81–89.

    Article  PubMed  CAS  Google Scholar 

  • Jira, W., Spiteller, G., Carson, W., & Schramm, A. (1998). Strong increase in hydroxy fatty acids derived from linoleic acid in human low density lipoproteins of atherosclerotic patients. Chemistry and Physics of Lipids, 91(1), 1–11.

    Article  PubMed  CAS  Google Scholar 

  • Larsen, B. T., Miura, H., Hatoum, O. A., Campbell, W. B., Hammock, B. D., Zeldin, D. C., et al. (2006). Epoxyeicosatrienoic and dihydroxyeicosatrienoic acids dilate human coronary arterioles via BK(Ca) channels: Implications for soluble epoxide hydrolase inhibition. American Journal of Physiology-Heart and Circulatory Physiology, 290(2), H491–H499. doi:10.1152/ajpheart.00927.2005.

    Article  PubMed  CAS  Google Scholar 

  • Li, H., Ruan, X. Z., Powis, S. H., Fernando, R., Mon, W. Y., Wheeler, D. C., et al. (2005). EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: Evidence for a PPAR-[gamma]-dependent mechanism. Kidney International, 67(3), 867–874.

    Article  PubMed  CAS  Google Scholar 

  • Libetta, C., Rampino, T., Palumbo, G., Esposito, C., & Dal Canton, A. (1997). Circulating serum lectins of patients with IgA nephropathy stimulate IL-6 release from mesangial cells. Journal of the American Society of Nephrology, 8(2), 208–213.

    PubMed  CAS  Google Scholar 

  • Menegatti, E., Roccatello, D., Fadden, K., Piccoli, G., De Rosa, G., Sena, L. M., et al. (1999). Gene expression of 5-lipoxygenase and LTA4 hydrolase in renal tissue of nephrotic syndrome patients. Clinical and Experimental Immunology, 116(2), 347–353.

    Article  PubMed  CAS  Google Scholar 

  • Mestecky, J., Hashim, O. H., & Tomana, M. (1995). Alterations in the IgA carbohydrate chains influence the cellular distribution of IgA1. Contributions to Nephrology, 111, 66–71. discussion 71-62.

    PubMed  CAS  Google Scholar 

  • Myllymaki, J., Syrjanen, J., Helin, H., Pasternack, A., Kattainen, A., & Mustonen, J. (2006). Vascular diseases and their risk factors in IgA nephropathy. Nephrology, Dialysis, Transplantation, 21(7), 1876–1882. doi:10.1093/ndt/gfl062.

    Article  PubMed  Google Scholar 

  • Negishi, M., Shimizu, H., Okada, S., Kuwabara, A., Okajima, F., & Mori, M. (2004). 9HODE stimulates cell proliferation and extracellular matrix synthesis in human mesangial cells via PPARgamma. Experimental biology and medicine (Maywood), 229(10), 1053–1060.

    CAS  Google Scholar 

  • Newman, J. W., Kaysen, G. A., Hammock, B. D., & Shearer, G. C. (2007). Proteinuria increases oxylipid concentrations in VLDL and HDL but not LDL particles in the rat. Journal of Lipid Research, 48(8), 1792–1800. doi:10.1194/jlr.M700146-JLR200.

    Article  PubMed  CAS  Google Scholar 

  • Obinata, H., Hattori, T., Nakane, S., Tatei, K., & Izumi, T. (2005). Identification of 9-hydroxyoctadecadienoic acid and other oxidized free fatty acids as ligands of the G protein-coupled receptor G2A. Journal of Biological Chemistry, 280(49), 40676–40683. doi:10.1074/jbc.M507787200.

    Article  PubMed  CAS  Google Scholar 

  • Parinyasiri, U., Ong-Ajyooth, L., Parichatikanond, P., Ong-Ajyooth, S., Liammongkolkul, S., & Kanyog, S. (2004). Effect of fish oil on oxidative stress, lipid profile and renal function in IgA nephropathy. Journal of the Medical Association of Thailand, 87(2), 143–149.

    PubMed  Google Scholar 

  • Peeraully, M. R., Sievert, H., Bullo, M., Wang, B., & Trayhurn, P. (2006). Prostaglandin D2 and J2-series (PGJ2, Delta12-PGJ2) prostaglandins stimulate IL-6 and MCP-1, but inhibit leptin, expression and secretion by 3T3-L1 adipocytes. Pflugers Archiv European Journal of Physiology, 453(2), 177–187. doi:10.1007/s00424-006-0118-x.

    Article  PubMed  CAS  Google Scholar 

  • Pettersson, E. E., Rekola, S., Berglund, L., Sundqvist, K. G., Angelin, B., Diczfalusy, U., et al. (1994). Treatment of IgA nephropathy with omega-3-polyunsaturated fatty acids: A prospective, double-blind, randomized study. Clinical Nephrology, 41(4), 183–190.

    PubMed  CAS  Google Scholar 

  • Rifai, A., Sakai, H., & Yagame, M. (1993). Expression of 5-lipoxygenase and 5-lipoxygenase activation protein in glomerulonephritis. Kidney International Supplements, 39, S95–S99.

    CAS  Google Scholar 

  • Roccatello, D., Picciotto, G., Torchio, M., Ropolo, R., Ferro, M., Franceschini, R., et al. (1993). Removal systems of immunoglobulin A and immunoglobulin A containing complexes in IgA nephropathy and cirrhosis patients. The role of asialoglycoprotein receptors. Laboratory Investigation, 69(6), 714–723.

    PubMed  CAS  Google Scholar 

  • Serhan, C. N., & Chiang, N. (2004). Novel endogenous small molecules as the checkpoint controllers in inflammation and resolution: Entree for resoleomics. Rheumatic Diseases Clinics of North America, 30(1), 69–95. doi:10.1016/S0889-857X(03)00117-0.

    Article  PubMed  Google Scholar 

  • Sulikowska, B., Manitius, J., Nieweglowski, T., Szydlowska-lysiak, W., & Rutkowski, B. (2002). The effect of therapy with small doses of mega-3 polyunsaturated fatty acid on renal reserve and metabolic disturbances in patients with primary IGA glomerulopathy. Polskie Archiwum Medycyny Wewnetrznej, 108(2), 753–760.

    PubMed  Google Scholar 

  • Sulikowska, B., Nieweglowski, T., Manitius, J., Lysiak-Szydlowska, W., & Rutkowski, B. (2004). Effect of 12-month therapy with omega-3 polyunsaturated acids on glomerular filtration response to dopamine in IgA nephropathy. American Journal of Nephrology, 24(5), 474–482.

    Article  PubMed  CAS  Google Scholar 

  • Swaminathan, S., Leung, N., Lager, D. J., Melton, L. J, 3rd, Bergstralh, E. J., Rohlinger, A., et al. (2006). Changing incidence of glomerular disease in Olmsted County, Minnesota: A 30-year renal biopsy study. Clinical Journal of the American Society of Nephrology, 1(3), 483–487. doi:10.2215/CJN.00710805.

    Article  PubMed  Google Scholar 

  • Syrjanen, J., Huang, X. H., Mustonen, J., Koivula, T., Lehtimaki, T., & Pasternack, A. (2000). Angiotensin-converting enzyme insertion/deletion polymorphism and prognosis of IgA nephropathy. Nephron, 86(2), 115–121.

    Article  PubMed  CAS  Google Scholar 

  • Taccone-Gallucci, M., Manca-di-Villahermosa, S., Battistini, L., Stuffler, R. G., Tedesco, M., & Maccarrone, M. (2006). N-3 PUFAs reduce oxidative stress in ESRD patients on maintenance HD by inhibiting 5-lipoxygenase activity. Kidney International, 69(8), 1450–1454.

    PubMed  CAS  Google Scholar 

  • Tager, A. M., Bromley, S. K., Medoff, B. D., Islam, S. A., Bercury, S. D., Friedrich, E. B., et al. (2003). Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment. Nature Immunology, 4(10), 982–990. doi:10.1038/ni970.

    Article  PubMed  CAS  Google Scholar 

  • Viswanathan, S., Hammock, B. D., Newman, J. W., Meerarani, P., Toborek, M., & Hennig, B. (2003). Involvement of CYP 2C9 in mediating the proinflammatory effects of linoleic acid in vascular endothelial cells. Journal of the American College of Nutrition, 22(6), 502–510.

    PubMed  CAS  Google Scholar 

  • Wang, L., Gill, R., Pedersen, T. L., Higgins, L. J., Newman, J. W., & Rutledge, J. C. (2009). Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation. Journal of Lipid Research, 50(2), 204–213. doi:10.1194/jlr.M700505-JLR200.

    Article  PubMed  CAS  Google Scholar 

  • Shearer, G. C., Harris, W. S., Pedersen, T. L., & Newman, J. W. (2009). Detection of omega-3 oxylipins in human plasma and response to treatment with omega-3 acid ethyl esters. Journal of Lipid Research, 51(8), 2074–2081. doi:10.1194/M900193-JLR200.

    Article  PubMed  Google Scholar 

  • Yang, J., Schmelzer, K., Georgi, K., & Hammock, B. D. (2009). Quantitative profiling method for oxylipin metabolome by liquid chromatography electrospray ionization tandem mass spectrometry. Analytical Chemistry, 81(19), 8085–8093. doi:10.1021/ac901282n.

    Article  PubMed  CAS  Google Scholar 

  • Ye, D., Zhang, D., Oltman, C., Dellsperger, K., Lee, H. C., & VanRollins, M. (2002). Cytochrome p-450 epoxygenase metabolites of docosahexaenoate potently dilate coronary arterioles by activating large-conductance calcium-activated potassium channels. Journal of Pharmacology and Experimental Therapeutics, 303(2), 768–776.

    Article  PubMed  CAS  Google Scholar 

  • Zhao, X., Yamamoto, T., Newman, J. W., Kim, I. H., Watanabe, T., Hammock, B. D., et al. (2004). Soluble epoxide hydrolase inhibition protects the kidney from hypertension-induced damage. Journal of the American Society of Nephrology, 15(5), 1244–1253.

    PubMed  CAS  Google Scholar 

  • Zivkovic, A. M., Wiest, M. M., Nguyen, U. T., Davis, R., Watkins, S. M., & German, J. B. (2009). Effects of sample handling and storage on quantitative lipid analysis in human serum. Metabolomics, 5(4), 507–516. doi:10.1007/s11306-009-0174-2.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors acknowledge Dr Danica Skibola for her support and help with clinical sample preparation, and C. J. Dillard with manuscript editing. This work was supported by The Center for Health and Nutrition Research (CHNR) Pilot Grant Program, National Institute of Diabetes and Digestive and Kidney Diseases grant R01 DK49368; The University of California Discovery Program (05GEB01NHB); the National Institute of Environmental Health Sciences (NIEHS) (P42ES004699), NIEHS R01 ES002710, and NIEHS Superfund Research Program P42 ES011269; the California Dairy Research Foundation; the CHARGE study (P01 ES11269); and partial support was provided by the American Asthma Association #09-0269. JY was supported by the Elizabeth Nash Memorial fellowship from the Cystic Fibrosis Research Inc. BDH is a George and Judy Marcus Senior Fellow of the American Asthma Foundation.

Author information

Authors and Affiliations

  1. Foods for Health Institute, Food Science & Technology Department, and Entomology Department, University of California, Davis, CA, USA

    Angela M. Zivkovic

  2. Department of Entomology, University of California, Davis, CA, USA

    Jun Yang, Katrin Georgi, Christine Hegedus & Malin L. Nording

  3. Foods for Health Institute, University of California, Davis, CA, USA

    Aifric O’Sullivan

  4. Foods for Health Institute, Department of Food Science and Technology, University of California, Davis, CA, USA

    J. Bruce German

  5. Scott & White Clinic, Temple, TX, USA

    Ronald J. Hogg

  6. Nephrology Division, Department of Medicine, University of California, Davis, CA, USA

    Robert H. Weiss

  7. Department of Interdisciplinary Health Sciences, Arizona School of Health Sciences, A.T. Still University, Mesa, AZ, USA

    Curt Bay

  8. Foods for Health Institute, Department of Entomology, University of California, Davis, CA, USA

    Bruce D. Hammock

Authors
  1. Angela M. Zivkovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katrin Georgi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christine Hegedus
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Malin L. Nording
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aifric O’Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. Bruce German
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ronald J. Hogg
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Robert H. Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Curt Bay
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bruce D. Hammock
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Angela M. Zivkovic.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zivkovic, A.M., Yang, J., Georgi, K. et al. Serum oxylipin profiles in IgA nephropathy patients reflect kidney functional alterations. Metabolomics 8, 1102–1113 (2012). https://doi.org/10.1007/s11306-012-0417-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11306-012-0417-5

Keywords

Search

Navigation