Gamma linolenic acid exerts anti-inflammatory and anti-fibrotic effects in diabetic nephropathy

Abstract

Background: Accumulating evidence suggests that an inflammatory mechanism contributes to the development and progression of diabetic nephropathy. Gamma linolenic acid (GLA), a member of polyunsaturated fatty acids (PUFAs), has been reported to have an anti-inflammatory effect by generating modulatory molecules for inflammatory responses. In addition, previous studies have demonstrated that GLA abrogates rheumatologic diseases and diabetic neuropathy via an anti-inflammatory mechanism. However, the effect of GLA on diabetic nephropathy has been largely unexplored.Purpose: This study was undertaken to investigate the effects of GLA on inflammation and extracellular matrix (ECM) synthesis in mesangial and tubular epithelial cells under diabetic conditions.Methods: In vivo, 32 Sprague-Dawley rats were injected either with diluent [n=16, control(C)] or streptozotocin intraperitoneally [n=16, diabetes(DM)], and 8 rats from control and diabetic groups were treated with evening primrose oil by gavage (450 mg/kg/day) for 3 months. In vitro, rat mesangial cells and NRK-52E cells were exposed to medium containing 5.6 mM glucose (NG), NG+24.4 mM mannitol (NG+M), and 30 mM glucose (HG) with or without GLA (10 or 100 M). Real-time PCR and Western blot were performed for intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), and fibronectin (FN) mRNA and protein expression, respectively. Immunohistochemical staining for ICAM-1 and FN, and Masson’s trichrome staining with renal tissue were also performed.Results: Twenty four-hour urinary albumin excretion was significantly increased in DM compared to C rats (p<0.05), and GLA treatment significantly reduced albuminuria in DM rats (p<0.05). ICAM-1, MCP-1, and FN mRNA and protein expression were significantly increased in DM compared to C kidney, and these increases were significantly abrogated by GLA treatment. In addition, the extent of glomerular and tubulointerstitial fibrosis assessed by Masson’s trichrome staining was significantly greater in DM relative to C kidney (p<0.005), and this change was significantly ameliorated by the administration of GLA (p<0.01). In vitro, GLA significantly inhibited the increases in MCP-1 mRNA expression and protein levels under high glucose conditions in HG-stimulated mesangial and tubular epithelial cells (p<0.05). ICAM-1 and FN expression showed a similar pattern to the expression of MCP-1.Conclusion: GLA attenuates not only inflammation via inhibiting enhanced MCP-1 and ICAM-1 expression but also ECM accumulation in diabetic nephropathy.