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[Protective effects of 15-methyl-lipoxin A4 on mesangioproliferative nephritis in rats]
Sheng-Hua Wu1, Pei-Yuan Liao, Ling Dong
1Department of Pediatrics, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
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.
Insights
15-methyl-lipoxin A4 (LXA4) effectively treats mesangioproliferative nephritis in rats by reducing proteinuria and glomerular inflammation. This protective effect is linked to the inhibition of key signaling pathways, including PI3-K/Akt1/p27(kip1)/cyclin, STAT3, and NF-kappaB.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Context:
- Mesangioproliferative nephritis is a kidney disease characterized by inflammation and cell proliferation in the glomerulus.
- Anti-Thy1.1 antibody-induced nephritis in rats serves as a model for studying human kidney diseases.
- Lipoxin A4 (LXA4) analogs are being investigated for their anti-inflammatory properties.
Purpose:
- To evaluate the therapeutic potential of 15-methyl-lipoxin A4 (LXA4) in a rat model of mesangioproliferative nephritis.
- To elucidate the underlying molecular mechanisms by which 15-methyl-LXA4 exerts its protective effects.
Summary:
- 15-methyl-LXA4 treatment significantly reduced proteinuria, glomerular leukocyte infiltration, and mesangial cell proliferation in nephritic rats.
- The compound inhibited the expression of pro-inflammatory cytokines IL-1beta and IL-6.
- 15-methyl-LXA4 modulated key signaling pathways, including PI3-K/Akt1/p27(kip1)/cyclin, STAT3, and NF-kappaB.
Impact:
- These findings suggest that 15-methyl-LXA4 holds promise as a novel therapeutic agent for mesangioproliferative nephritis.
- The study identifies specific molecular targets for potential drug development in kidney disease treatment.