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.
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