Mechanical Stretch Induces Monocyte Chemoattractant Activity via an NF-κB-Dependent Monocyte Chemoattractant Protein-1-Mediated Pathway in Human Mesangial Cells

Abstract

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.

Monocyte chemoattractant protein-1 has prosclerotic effects both in a mouse model of experimental diabetes and in vitro in human mesangial cells

“…These data, indicating that NF-κB mediates MCP-1-induced TGF-β1 production, are in line with previous studies showing an NF-κB binding site in the TGF-β1 promoter region [29] and MCP-1-induced NF-κB activation in HMCs primed with IFN-γ [42]. Interestingly, we have recently shown that MCP-1 production in response to high glucose and stretch in HMCs is also mediated by an NF-κB-dependent mechanism [4]. The intracellular pathway mediating MCP-1/ CCR2-induced NF-κB activation remains undetermined; however, the signalling molecules phosphatidylinositol 3-kinase, Rho and janus kinase 2 are known to be activated by the MCP-1/CCR2 system [43][44][45] and can lead to NF-κB activation [46][47][48] in other cell types.…”

“…Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine produced by activated monocytes and a variety of mesenchymal cells. In vitro, mesangial cell exposure to stretch and high glucose induces MCP-1 production resulting in monocyte chemotaxis [4]. In vivo, MCP-1 is overproduced in the glomeruli in experimental diabetes, an event paralleled by monocyte infiltration [5,6].…”

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

“…43 These effects, which were further magnified by simultaneous exposure of mesangial cells to stretch and high glucose, were mediated by nuclear factor-kappa B (NF-kB). 44 Furthermore, both stretch and MCP-1 independently induce intercellular adhesion molecule-1 (ICAM-1) expression. 43 This would increase phagocytic leukocyte adhesion to mesangial cells 44 and amplify the inflammatory cascade 45 and may contribute to glomerular injury by inducing the release of cytotoxic reactive oxygen species.…”

“…44 Furthermore, both stretch and MCP-1 independently induce intercellular adhesion molecule-1 (ICAM-1) expression. 43 This would increase phagocytic leukocyte adhesion to mesangial cells 44 and amplify the inflammatory cascade 45 and may contribute to glomerular injury by inducing the release of cytotoxic reactive oxygen species. 46 Angiotensin II (Ang II), a powerful vasoconstrictor and trophic hormone, is central to renal damage in diabetes.…”

Stretch-induced human myometrial cytokines enhance immune cell recruitment via endothelial activation

“…Mechanical stretch has been widely demonstrated as an inducer of cytokine synthesis in different tissues. 20,21 In particular, many have reported the ability of various uterine cell types such as fetal membrane epithelial cells, uterine myocytes and cervical fibroblasts to secrete cytokines following mechanical stretch stimulus. 22 Using murine models of gestation, we have demonstrated that rat and mouse myometrial smooth muscle cells (SMCs) are capable of producing multiple cytokines under the influence of uterine stretch imposed by the growing fetus around the time of labour.…”