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The role of lipoproteins in the development of glomerulosclerosis y Edward G. Lynn

by Lynn, Edward G

Abstract (Summary)
(Uncorrected OCR) Abstract of thesis entitled The Role of Lipoproteins in the Development of Glomerulosclerosis submitted by Edward G. Lynn for the degree of Doctor of Philosophy at the University of Hong Kong in September 2000 Hypertriglyceridemia is the most common plasma lipid abnormality in adult patients and children with renal failure. A large number of dialysis patients have high levels of triglycerides. Non-diabetic patients with progressive renal insufficiency present with elevated levels of both triglycerides and VLDL. In addition, chronic renal failure is often associated with hypertriglyceridemia. Furthermore, elevated plasma levels of triglyceride-rich VLDL are associated with increased risk for glomerulosclerosis. Another condition that may lead to glomerulosclerosis is familial lecithin:cholesterol acyltransferase (LCAT) deficiency, a rare genetic disorder. The clinical symptoms of familial LCAT deficiency include corneal opacities, hemolytic anemia, proteinuria and subsequent renal failure. One important feature of LCAT deficiency is the presence of lipoprotein-X (Lp-X) in patientsplasma. Many of these patients develop glomerulosclerosis. A key feature in the pathogenesis of glomerulosclerosis is the presence of foam cells derived from the infiltration of circulating monocytes in affected glomeruli. Mesangial cells can synthesize and secrete monocyte chemoattractant protein-1 (MCP-1), an important chemoattractant for monocytes. The objective of this study was to investigate the role of VLDL and Lp-X on monocyte chemotaxis and the mechanisms involved. VLDL was isolated from the plasma of healthy volunteers. Lp-X was isolated from the plasma of a LCAT deficient patient. Mesangial cells were isolated from male Sprague-Dawley rats. MCP-1 protein and mRNA levels were determined by Western immunoblotting and semi-quantitative RT-PCR, respectively. Conditioned media collected from mesangial cells treated with either VLDL or Lp-X stimulated THP-1 monocyte chemotaxis in a dose-dependent manner (250 640% and 165 200%, respectively). The elevated monocyte chemotaxis was subsequently accompanied by increased monocyte adhesion to mesangial cells (Lp-X, 132 214%; VLDL, 252 426%). VLDL (100 300 ?/mL)-induced monocyte chemotaxis was associated with significantly elevated MCP-1 mRNA levels (113 153%) and protein secretion (54 285 ng/well) in mesangial cells. VLDL-induced monocyte chemotaxis was blocked by a protein kinase C inhibitor (staurosporine) as well as a calcium channel blocker (diltiazem). Treatment of mesangial cells with Lp-X (50 100 nmol/mL) stimulated mesangial cell MCP-1 protein secretion (233 375%) and MCP-1 mRNA expression (137 220%). Lp-X-induced MCP-1 expression was abolished by staurosporine. Lp-X increased both intracellular diacylglycerol levels (123 158%) and phosphatidylcholine-specific phospholipase C activity (169 315%). In conclusion, our results demonstrate that VLDL and Lp-X may contribute to the infiltration of monocytes in affected glomeruli via a mechanism involving MCP-1 expression in mesangial cells. Hence, both VLDL and Lp-X may play an important role in the development of glomerulosclerosis in these patients.
Bibliographical Information:

Advisor:

School:The University of Hong Kong

School Location:China - Hong Kong SAR

Source Type:Master's Thesis

Keywords:lipoproteins hypertriglyceridemia

ISBN:

Date of Publication:01/01/2000

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