[Protective effects of 15-methyl-lipoxin A4 on mesangioproliferative nephritis in rats].
OBJECTIVE
To investigate the protective effects of 15-methyl-lipoxin A4 (LXA4) 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 (ER4) in 20 rats. Ten nephritic rats were injected with 15-methyl-LXA4 at 10 minutes before ER4 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)-1beta and IL-6 protein or mRNA in glomeruli were determined by radioimmunoassay or RT-PCR, respectively. Phosphorylated phosphoinositide 3-kinase (PI3-K), Akt1 and p27(kip1) in glomeruli were analyzed by Western Blot. Activities of nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription 3 (STAT3) in glomeruli were assessed by electrophoretic mobility shift assay (EMSA).


RESULTS
There were increases in glomerular infiltration of leukocyte, expressions of IL-1beta and IL-6 protein and mRNA, and activities of NF-kappaB 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, Akt1 and STAT3, and reduced p27(kip1) expression were found on day 4 after nephritis induction. 15-Methyl-LXA4 treatment significantly reduced the proteinuria, glomerular infiltration of leukocyte, expressions of IL-1beta and IL-6 protein and mRNA, score of mesangial proliferation, glomerular PCNA positive cells, activities of phosphorylated PI3-K, Akt1, NF-kappaB and STAT3, and increased the p27(kip1) expression.


CONCLUSIONS
15-Methyl-LXA4 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/Akt1/p27(kip1)/cyclin pathway, STAT3 and NF-kappaB pathway-dependent signal transduction.
Wu
Sheng-Hua
SH
Department of Pediatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Liao
Pei-Yuan
PY
Dong
Ling
L
Jiang
Xin-You
XY
D000818:Animals; D004247:DNA / Q000378:metabolism; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative / Q000188:drug therapy*; D007375:Interleukin-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D044045:Lipoxins / Q000627:therapeutic use*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
C512487:15-methyl-lipoxin A4; D007375:Interleukin-1; D015850:Interleukin-6; D044045:Lipoxins; D016328:NF-kappa B; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases