Signal transduction involved in protective effects of 15(R/S)-methyl- lipoxin A4 on mesangioproliferative nephritis in rats

Studies have shown that lipoxin A4 (LXA4) inhibited proliferation of mesangial cells in vitro induced by platelet-derived growth factor, epidermal growth factor, leukotriene D4 or tumor necrosis factor-α. In this study, we investigated the protective effects of 15(R/S)-methyl-LXA4 on mesangioproliferative nephritis in rats and the signal transduction involved in actions of 15(R/S)-methyl-LXA4. Mesangioproliferative nephritis was induced by a single intravenous injection of the mouse monoclonal anti-Thy1.1 antibodies. The nephritic rats were treated by intravenous injection of 15(R/S)-methyl-LXA4 every 8 h until the rats were sacrificed. There were increments in glomerular infiltration of leukocytes, expressions of protein and mRNA of interleukin (IL)-1β and IL-6, activities of nuclear factor-κB (NF-κB) in nephritic rats from day 1 to 4 after induction of nephritis. The enhanced proteinuria, proliferation score of mesangial cells, glomerular proliferating cell nuclear antigen (PCNA) positive cells, activities of phosphorylated phosphoinositide 3-kinase (PI3-K), Akt1, α-smooth muscle actin (α-SMA) and signal transducer and activator of transcription 3(STAT3), and reduced expression of p27kip1 were found on day 4 after induction of nephritis. Treatment of nephritic rats with 15(R/S)-methyl-LXA4 significantly reduced the protenuria, glomerular infiltration of leukocyte, expressions of protein and mRNA of IL-1β and IL-6, proliferation score of mesangial cells, glomerular PCNA positive cells, activities of phosphorylated PI3-K, Akt1, α-SMA, NF-κB and STAT3, and ameliorated the decrement in p27kip1 induced by anti-Thy1.1 antibodies. Protective effects of 15(R/S)-methyl-LXA4 on nephritis induced by anti-Thy1.1 antibodies were related to PI3-K/Akt1/p27kip1/cyclin pathway, STAT3 and NF-κB pathway-dependent signal transduction.