Abstract:OBJECTIVE: To investigate the protective effects of 15-methy-lipoxin A_4 (LXA_4 ) on mesangioproliferative nephritis in rats and the possible mechanisms. METHODS: Mesangioproliferative nephritis was induced by a single intravenous injection of the mouse monoclonal anti-Thy1.1 antibodies (ER_4) in 20 rats. Ten nephritic rats were injected with 15-methy-LXA_ 4 at 10 minutes before ER_4 antibody injection and then 8-hourly until the rats were sacrificed on day 4 after nephritis induction. The nephritis was evidenced by presence of proteinuria, histologic examination with light microscopy, infiltrating leukocyte assessed by immunofluorescence microscopy, and mesangial cell proliferation assessed by proliferation scoring and by immunohistochemical staining of proliferating cell nuclear antigen (PCNA). Expressions of interleukin (IL)-1β and IL-6 protein or mRNA in glomeruli were determined by radioimmunoassay or RT-PCR, respectively. Phosphorylated phosphoinositide 3-kinase (PI3-K), Akt_1 and p27 kip1 in glomeruli were analyzed by Western Blot. Activities of nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT_3) in glomeruli were assessed by electrophroretic mobility shift assay (EMSA). Results: There were increases in glomerular infiltration of leukocyte, expressions of IL-1β and IL-6 protein and mRNA, and activities of NF-κB in nephritic rats between days 1 and 4 after nephritis induction. The enhanced proteinuria, score of mesangial proliferation, glomerular PCNA positive cells, activities of phosphorylated PI3-K, Akt_1 and STAT_3, and reduced p27 kip1 expression were found on day 4 after nephritis induction. 15-methy-LXA_ 4 treatment significantly reduced the proteinuria, glomerular infiltration of leukocyte, expressions of IL-1β and IL-6 protein and mRNA, score of mesangial proliferation, glomerular PCNA positive cells, activities of phosphorylated PI3-K, Akt_1, NF-κB and STAT_3, and increased the p27 kip1 expression. Conclusions: 15-methy-LXA_ 4 can markedly inhibit the proteinuria, glomerular inflammation, and mesangial cell proliferation induced by anti-Thy1.1 antibodies. The inhibition effects are related to PI3-K/Akt_1/p27 kip1 /cyclin pathway, STAT_3 and NF-κB pathway-dependent signal transduction.
