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Mechanical Stretch Induces Monocyte Chemoattractant Activity via an NF-B-Dependent Monocyte Chemoattractant Protein-1-Mediated Pathway in Human Mesangial Cells: Inhibition by Rosiglitazone

Gabriella Gruden^*, Giorgia Setti^*, Anthea Hayward^*, David Sugden, Sara Duggan^*, Davina Burt^*, Robin E. Buckingham^*, Luigi Gnudi^* and Giancarlo Viberti^*

^* Department of Diabetes and Endocrinology, Cardiovascular Division, and Endocrinology and Reproduction Research Group, King’s College, London, United Kingdom

Address correspondence to: Dr. Gabriella Gruden, Department of Internal Medicine, C/so AM Dogliotti 14, Turin, Italy. Phone: 39-011-6336448; Fax: 39-011-6634751; E-mail: ggruden{at}hotmail.com

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 IB-NF-B pathway, and NF-B inhibition, with the use of the specific inhibitor SN50, completely abolished stretch-induced MCP-1, indicating that stretch-induced MCP-1 was NF-B dependent. The addition of rosiglitazone significantly diminished stretch-induced NF-B activation, MCP-1 production, and monocyte chemotaxis. In conclusion, stretching of mesangial cells stimulates their monocyte chemoattractant activity via an NF-B-mediated, MCP-1-dependent pathway, and this effect is prevented by rosiglitazone.

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