Eicosapentaenoic acid ameliorates diabetic nephropathy of type 2 diabetic KKAy/Ta mice: involvement of MCP-1 suppression and decreased ERK1/2 and p38 phosphorylation.

BACKGROUND Previous studies reported that eicosapentaenoic acid (EPA) was effective against any renal diseases including diabetic nephropathy. Monocyte chemoattractant protein-1 (MCP-1) is a regulating macrophage recruitment protein, which is up-regulated in patients with diabetic nephropathy. The objectives of the present study were to evaluate the effects of EPA including renal MCP-1 expression in diabetic KKAy/Ta mice, MCP-1 production and signal transduction in mouse mesangial cells (MMCs). METHODS KKAy/Ta mice were injected with EPA ethyl ester (1 g/kg/day) intraperitoneally. Immunohistochemical staining of MCP-1, F4/80, phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) and phospho-p38 in the renal sections were performed. EPA or specific inhibitors were incorporated in MMCs, and the levels of supernatant MCP-1 were measured. The effect of EPA on ERK1/2, c-jun NH2-terminal kinase (JNK), p38 or phosphoinositide 3-kinase (PI3K) activity in MMCs was examined using Western blot. RESULTS EPA decreased the levels of serum triglycerides, leptin, urinary albumin and MCP-1, and improved glucose intolerance, mesangial matrix accumulation and tubulointerstitial fibrosis in KKAy/Ta mice. Immunohistochemical staining of MCP-1 and F4/80 in the glomeruli and tubulointerstitial regions was decreased in the EPA-treated group. EPA and specific inhibitors of ERK1/2, JNK and PI3K decreased levels of MCP-1 in MMCs. EPA suppressed phosphorylation of ERK1/2 and p38 in MMCs, and decreased p-ERK positive cells in glomeruli of KKAy/Ta mice. CONCLUSIONS EPA ameliorates diabetic nephropathy of type 2 diabetic KKAy/Ta mice. We propose that the observed down-regulation of MCP-1 is critically involved in the beneficial effect of EPA, probably in concert with improvement of other clinical parameters.