G Setti

Mechanical stretch induces monocyte chemoattractant activity via an NF-kappaB-dependent monocyte chemoattractant protein-1-mediated pathway in human mesangial cells: inhibition by rosiglitazone

Hemodynamic abnormalities are important in the pathogenesis of the glomerular damage in diabetes. Glomerular macrophage infiltration driven by the chemokine monocyte chemoattractant protein-1 (MCP-1) is an early event in diabetic nephropathy. The thiazolidinedione rosiglitazone ameliorates albumin excretion rate in diabetic patients with microalbuminuria and has anti-inflammatory properties, raising the possibility of a relationship between its renoprotective and anti-inflammatory activity. Investigated was whether mesangial cell stretching, mimicking in vitro glomerular capillary hypertension, enhances MCP-1 expression and monocyte chemoattractant activity. The effect of the combination of stretch with high glucose on MCP-1 production was studied and, finally, the effect of rosiglitazone on these processes was assessed. Stretching of human mesangial cells significantly enhanced their monocyte chemoattractant activity. This effect was mediated by MCP-1 as it was paralleled by a significant rise in both MCP-1 mRNA and protein levels and was completely abolished by MCP-1 blockade. Combined exposure to both stretch and high glucose further increased MCP-1 production. Stretch activated the IkappaB-NF-kappaB pathway, and NF-kappaB inhibition, with the use of the specific inhibitor SN50, completely abolished stretch-induced MCP-1, indicating that stretch-induced MCP-1 was NF-kappaB dependent. The addition of rosiglitazone significantly diminished stretch-induced NF-kappaB activation, MCP-1 production, and monocyte chemotaxis. In conclusion, stretching of mesangial cells stimulates their monocyte chemoattractant activity via an NF-kappaB-mediated, MCP-1-dependent pathway, and this effect is prevented by rosiglitazone.

Peroxisome Proliferator-Activated Receptor-γ Agonist Rosiglitazone Prevents Albuminuria but Not Glomerulosclerosis in Experimental Diabetes

Backgrounds/Aims:Renal inflammation and nephrin downregulation contribute to albuminuria in diabetes. We studied, in streptozotocin-induced diabetic rats, the effect of rosiglitazone (RSG), a peroxisome proliferator-activated receptor-γ agonist, on renal macrophage infiltration, MCP1, and nephrin expression in relation to albuminuria. Methods: We investigated control and diabetic rats treated or untreated with RSG. Animals were sacrificed at 1, 3, and 9 months. Renal MCP1 and nephrin expression were studied by immunoblotting, renal macrophage infiltration by immunohistochemistry, and albuminuria by ELISA. Electron microscopy was used to assess glomerular ultrastructural morphology. In vitroexperiments were conducted in isolated cultured rat glomeruli. Results: Glycaemic control was similar in diabetic rats treated and untreated with RSG, and blood pressure was comparable in all groups. RSG prevented diabetes-induced albuminuria at 9 months, and renal macrophage infiltration and MCP1 upregulation at 3 and 9 months. Diabetes-mediated nephrin downregulation was abolished by RSG. Diabetes-induced glomerulosclerosis, glomerular basement membrane thickening, and foot process fusion were not affected by RSG. In isolated glomeruli, MCP1 directly induced nephrin downregulation and this was prevented by RSG. RSG had no effect on nephrin expression. Conclusion: RSG prevents albuminuria and nephrin downregulation in experimental diabetes independently of glycaemic and blood pressure control. This effect likely occurs via correction of diabetes-induced inflammatory processes.