The goal of this research will be to understand specific mechanisms by which dietary polyunsaturated fatty acids (n-3 PUFA) in marine and plant oils impair development and progression of immunoglobulin A nephropathy (IgAN). Although IgAN is the most common glomerulonephritis worldwide, effective treatments for it remain elusive. Fish oil consumption has recently shown promise in retarding disease progression and renal failure in IgAN patients. An experimental mouse model is now available in which immunopathological hallmarks of IgAN are induced by dietary exposure to the mycotoxin vomitoxin (VT). Interestingly, replacement of corn oil in a semi-purified diet with menhaden fish oil markedly impairs immunopathogenesis in this model. The sequential activation of mitogen-activated protein kinases (MAPKs), up-regulation of interleukin-6 (IL-6) gene expression and polyclonal activation of IgA-secreting cells appear to be critical early events in VT-induced IgAN. The guiding hypothesis for this project is that ingestion of n-3 PUFA in fish oil attenuates VT-induced IgAN by interfering with upstream regulation of IL-6 gene expression.
Five specific aims are proposed.
In AIM 1, a sub-chronic VT feeding model will be used to determine the capacity of feeding fish oil or the n-3 PUFAs, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), to attenuate VT-induced IgAN markers.
In AIM 2, an acute VT exposure model will be used to evaluate the in vivo and ex vivo effects of feeding fish oil on IL-6 and IgA expression.
In AIM 3, the role of transcription in n-3 PUFA-attenuated IL-6 expression will be assessed in VT-treated macrophage cultures by measuring transcription factor binding and nuclear runoff of IL-6 mRNA.
In AIM 4, the role of post-transcriptional mechanisms in n-3 PUFA-attenuated IL-6 expression will be evaluated by measuring IL-6 mRNA stability in macrophage cultures.
In AIM 5, the effects of n-3 PUFAs on activation of the MAPKs SAPK/JNK 1/2, ERK1/2 and p38 will be assessed in macrophages cultured with VT. Long-term impacts of increased mechanistic understanding of n-PUFA effects in this model may include improved nutritional and pharmacological strategies for inhibiting the progression of IgAN and potentially other autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK058833-04
Application #
6688288
Study Section
Special Emphasis Panel (ZRG1-SSS-T (02))
Program Officer
May, Michael K
Project Start
2001-02-01
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2005-12-31
Support Year
4
Fiscal Year
2004
Total Cost
$217,560
Indirect Cost
Name
Michigan State University
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824
Pestka, James J; Vines, Laura L; Bates, Melissa A et al. (2014) Comparative effects of n-3, n-6 and n-9 unsaturated fatty acid-rich diet consumption on lupus nephritis, autoantibody production and CD4+ T cell-related gene responses in the autoimmune NZBWF1 mouse. PLoS One 9:e100255
Kobayashi-Hattori, Kazuo; Amuzie, Chidozie J; Flannery, Brenna M et al. (2011) Body composition and hormonal effects following exposure to mycotoxin deoxynivalenol in the high-fat diet-induced obese mouse. Mol Nutr Food Res 55:1070-8
Flannery, Brenna M; Wu, Wenda; Pestka, James J (2011) Characterization of deoxynivalenol-induced anorexia using mouse bioassay. Food Chem Toxicol 49:1863-9
Pestka, James J (2010) n-3 polyunsaturated fatty acids and autoimmune-mediated glomerulonephritis. Prostaglandins Leukot Essent Fatty Acids 82:251-8
Bae, Heekyong; Gray, Jennifer S; Li, Maoxiang et al. (2010) Hematopoietic cell kinase associates with the 40S ribosomal subunit and mediates the ribotoxic stress response to deoxynivalenol in mononuclear phagocytes. Toxicol Sci 115:444-52
Bae, Hee Kyong; Shinozuka, Junko; Islam, Zahidul et al. (2009) Satratoxin G interaction with 40S and 60S ribosomal subunits precedes apoptosis in the macrophage. Toxicol Appl Pharmacol 237:137-45
Shi, Yuhui; Porter, Katie; Parameswaran, Narayanan et al. (2009) Role of GRP78/BiP degradation and ER stress in deoxynivalenol-induced interleukin-6 upregulation in the macrophage. Toxicol Sci 109:247-55
Shi, Yuhui; Pestka, James J (2009) Mechanisms for suppression of interleukin-6 expression in peritoneal macrophages from docosahexaenoic acid-fed mice. J Nutr Biochem 20:358-68
Li, Maoxiang; Pestka, James J (2008) Comparative induction of 28S ribosomal RNA cleavage by ricin and the trichothecenes deoxynivalenol and T-2 toxin in the macrophage. Toxicol Sci 105:67-78
Pestka, James J; Amuzie, Chidozie J (2008) Tissue distribution and proinflammatory cytokine gene expression following acute oral exposure to deoxynivalenol: comparison of weanling and adult mice. Food Chem Toxicol 46:2826-31

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