Signal transduction involved in protective effects of 15(R/S)-methyl- lipoxin A(4) on mesangioproliferative nephritis in rats.
Studies have shown that lipoxin A(4) (LXA(4)) inhibited proliferation of mesangial cells in vitro induced by platelet-derived growth factor, epidermal growth factor, leukotriene D(4) or tumor necrosis factor-alpha. In this study, we investigated the protective effects of 15(R/S)-methyl-LXA(4) on mesangioproliferative nephritis in rats and the signal transduction involved in actions of 15(R/S)-methyl-LXA(4). 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-LXA(4) every 8h until the rats were sacrificed. There were increments in glomerular infiltration of leukocytes, expressions of protein and mRNA of interleukin (IL)-1beta and IL-6, activities of nuclear factor-kappaB (NF-kappaB) 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), Akt(1), alpha-smooth muscle actin (alpha-SMA) and signal transducer and activator of transcription 3(STAT(3)), and reduced expression of p27(kip1) were found on day 4 after induction of nephritis. Treatment of nephritic rats with 15(R/S)-methyl-LXA(4) significantly reduced the protenuria, glomerular infiltration of leukocyte, expressions of protein and mRNA of IL-1beta and IL-6, proliferation score of mesangial cells, glomerular PCNA positive cells, activities of phosphorylated PI3-K, Akt(1), alpha-SMA, NF-kappaB and STAT(3), and ameliorated the decrement in p27(kip1) induced by anti-Thy1.1 antibodies. Protective effects of 15(R/S)-methyl-LXA(4) on nephritis induced by anti-Thy1.1 antibodies were related to PI3-K/Akt(1)/p27(kip1)/cyclin pathway, STAT(3) and NF-kappaB pathway-dependent signal transduction.
Wu
Sheng-Hua
SH
Department of Pediatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China. kad-yc@163.com
Wu
Xiang-Hua
XH
Liao
Pei-Yuan
PY
Dong
Ling
L
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism; D015432:Glomerulonephritis, Membranoproliferative / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D044045:Lipoxins / Q000737:chemistry / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D018800:Thy-1 Antigens / Q000276:immunology
D000199:Actins; D000906:Antibodies; D050760:Cyclin-Dependent Kinase Inhibitor p27; D053583:Interleukin-1beta; D015850:Interleukin-6; D044045:Lipoxins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D018800:Thy-1 Antigens; C493962:Cdkn1b protein, rat; C040527:lipoxin A4; C498862:Acta2 protein, rat