ω-3 PUFAs inhibited necroptosis of mesangial cells in a mouse model of systemic lupus erythematosus

In this study, we aimed to investigate the effects of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) on necroptosis of mesangial cells in systemic lupus erythematosus (SLE). 16-week-old female MRL/lpr mice were used as an animal model of SLE and were randomly divided into three groups: control group, necroptosis inhibitor treatment group, and ω-3 PUFAs treatment group. The mice were administered ω-3 PUFAs or the same volume of normal saline by oral gavage every other day for 4 weeks. Mice in the necroptosis inhibitor treatment group were administered Nec-1 (a necroptosis inhibitor) via intraperitoneal injection once daily for 3 weeks. After treatment, spleens and perirenal lymph nodes were harvested and weighed. Serum anti-dsDNA levels were measured by enzyme-linked immunosorbent assay (ELISA). Serum creatinine, blood urea nitrogen, and urinary protein levels were quantified. Renal pathology was evaluated using H&E and PAS staining. Renal IgG and C3 deposition was detected by immunofluorescence staining. Necroptosis-associated proteins were determined by immunofluorescence and Western blotting. Mesangial cells were treated with TNF-α, SM164, and Z-VAD-FMK to induce necroptosis and then supplemented with ω-3 PUFAs or Nec-1, respectively. The necroptosis of mesangial cells was assessed by Western blot, immunofluorescence staining, and flow cytometry. The inflammatory cytokines of mesangial cells were measured by RT-qPCR. ω-3 polyunsaturated fatty acids significantly ameliorated SLE-like symptoms in MRL/lpr mice, including attenuating splenomegaly and lymphadenopathy, alleviating renal pathology and lymphocyte infiltration, and decreasing renal immune complex deposition. Serum creatinine, blood urea nitrogen, and urinary protein levels were significantly down-regulated. Furthermore, ω-3 PUFAs treatment decreased inflammatory cytokines and inhibited necroptosis of mesangial cells in the kidneys of MRL/lpr mice. In vitro experiments demonstrated that ω-3 PUFAs inhibited necroptosis and reduced the release of inflammatory cytokines in mesangial cells. The results demonstrated that ω-3 PUFAs ameliorated the symptoms and attenuated necroptosis in renal mesangial cells in SLE mice. These findings suggest that ω-3 PUFAs might represent a novel therapeutic strategy for the treatment of SLE.