E G Lynn1, Y L Siow, K O. 1. Department of Pharmacology, Faculty of Medicine, University of Hong Kong, Hong Kong, China.
Abstract
BACKGROUND: Elevated plasma levels of very low-density lipoprotein (VLDL) are associated with an increased risk for focal glomerulosclerosis, which is analogous to atherosclerosis. One feature of focal glomerulosclerosis is the presence of foam cells derived from the infiltration of circulating monocytes. Mesangial cells are able to express monocyte chemoattractant protein-1 (MCP-1). In this study, the ability of VLDL to stimulate MCP-1 expression in mesangial cells and consequent monocyte adhesion was investigated. METHODS: For adhesion studies, mesangial cells isolated from Sprague-Dawley rats were treated with VLDL for six hours, followed by a one-hour incubation with Tamm-Horsfall protein-1 (THP-1) cells. Mesangial MCP-1 mRNA levels were determined by reverse transcription-polymerase chain reaction. MCP-1 protein was determined by solid-phase immunoassay. RESULTS: VLDL (100 to 300 microg/mL) significantly enhanced the expression and secretion of MCP-1 (54 to 285 ng/well) in mesangial cells. Such an effect was accompanied by the increased adhesion of monocytes to mesangial cells and later the formation of foam cells from monocytes after ingesting excessive amounts of VLDL lipids. VLDL-induced MCP-1 expression and monocyte adhesion were blocked by a protein kinase C inhibitor (staurosporine), as well as a calcium channel blocker (diltiazem). CONCLUSIONS: Our results demonstrate that elevated levels of VLDL, through the action of MCP-1, may contribute to the infiltration of monocytes into the mesangium and subsequent foam cell formation. Hence, VLDLs may play a role in the pathogenesis of focal glomerulosclerosis. One of the mechanisms of such effect may be mediated through the calcium-dependent protein kinase C pathway.
BACKGROUND: Elevated plasma levels of very low-density lipoprotein (VLDL) are associated with an increased risk for focal glomerulosclerosis, which is analogous to atherosclerosis. One feature of focal glomerulosclerosis is the presence of foam cells derived from the infiltration of circulating monocytes. Mesangial cells are able to express monocyte chemoattractant protein-1 (MCP-1). In this study, the ability of VLDL to stimulate MCP-1 expression in mesangial cells and consequent monocyte adhesion was investigated. METHODS: For adhesion studies, mesangial cells isolated from Sprague-Dawley rats were treated with VLDL for six hours, followed by a one-hour incubation with Tamm-Horsfall protein-1 (THP-1) cells. Mesangial MCP-1 mRNA levels were determined by reverse transcription-polymerase chain reaction. MCP-1 protein was determined by solid-phase immunoassay. RESULTS:VLDL (100 to 300 microg/mL) significantly enhanced the expression and secretion of MCP-1 (54 to 285 ng/well) in mesangial cells. Such an effect was accompanied by the increased adhesion of monocytes to mesangial cells and later the formation of foam cells from monocytes after ingesting excessive amounts of VLDLlipids. VLDL-induced MCP-1 expression and monocyte adhesion were blocked by a protein kinase C inhibitor (staurosporine), as well as a calcium channel blocker (diltiazem). CONCLUSIONS: Our results demonstrate that elevated levels of VLDL, through the action of MCP-1, may contribute to the infiltration of monocytes into the mesangium and subsequent foam cell formation. Hence, VLDLs may play a role in the pathogenesis of focal glomerulosclerosis. One of the mechanisms of such effect may be mediated through the calcium-dependent protein kinase C pathway.
Authors: Xianghong Zhu; Andrew M Herzenberg; Mohammad Eskandarian; Graham F Maguire; James W Scholey; Philip W Connelly; Dominic S Ng Journal: Am J Pathol Date: 2004-10 Impact factor: 4.307