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Data from: Lipidome modulation by dietary omega-3 polyunsaturated fatty acid supplementation or selective soluble epoxide hydrolase inhibition suppresses rough LPS-accelerated glomerulonephritis in lupus-prone mice

Abstract

Lipopolysaccharide (LPS)-accelerated autoimmune glomerulonephritis (GN) in lupus-prone NZBWF1 mice is a preclinical model that is potentially applicable for investigating lipidome-modulating interventions. LPS can be expressed as one of two chemotypes: smooth LPS (S-LPS) and rough LPS (R-LPS) which is devoid of O-antigen polysaccharide sidechain. Since these chemotypes differentially affect TLR4-mediated immune cell responses, these differences may influence GN induction. Therefore, we initially compared the effects of subchronic i.p. injection for 5 wk with 1) Salmonella S-LPS, 2) Salmonella R-LPS, or 3) saline vehicle (VEH) (Study 1) in female NZBWF1 mice. R-LPS induced robust elevations in blood urea nitrogen, proteinuria, and hematuria that were not evident in VEH- or S-LPS-treated mice. Histopathologic examination of R-LPS-treated mice one week after final injection further revealed more robust hypertrophy, hyperplasia, thickened membranes, lymphocytic accumulation containing B and T cells, and glomerular IgG deposition consistent with GN but not in VEH- or S-LPS-treated groups. R-LPS but not S-LPS induced spleen enlargement with lymphoid hyperplasia as well as modest inflammatory cell recruitment in the liver. We next employed our optimized R-LPS model to discern the impact of two lipidome-modulating interventions, omega-3 polyunsaturated fatty acid (PUFA) supplementation and soluble epoxide hydrolase (sEH) inhibition, on GN (Study 2). Specifically, the effects of consuming the omega-3 PUFA docosahexaenoic acid (DHA) (10 g/kg diet) and/or the sEH inhibitor TPPU (22.5 mg/kg diet) on R-LPS triggering were compared. Resultant blood fatty acid profiles and epoxy fatty acid concentrations reflected the anticipated DHA- and TPPU-mediated lipidome changes. The relative rank order of R-LPS-induced GN severity among groups fed experimental diets based on proteinuria, hematuria, histopathologic scoring, and glomerular IgG deposition was: VEH/CON < R-LPS/DHA ≈ R-LPS/TPPU <<< R-LPS/ TPPU+DHA ≈ R-LPS/CON. These interventions had modest to negligible effects on R-LPS-induced splenomegaly, plasma antibody responses, liver inflammation, and inflammation-associated kidney gene expression. Collectively, our results show for the first time that absence of O-antigenic polysaccharide in R-LPS is critical to accelerated GN in lupus-prone mice. Furthermore, intervention by lipidome modulation through DHA feeding or sEH inhibition suppressed R-LPS-induced GN; however, these ameliorative effects were greatly diminished upon combining the treatments.