Fernando, Rehan Laksen; (1998) The interaction of modified low density lipoproteins with glomerular mesangial cell and its potential influence on glomerulosclerosis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Focal segmental glomerulosclerosis is the final result of a number of interrelated events leading to permanent glomerular injury. It is a feature of many chronic progressive renal diseases. Glomerulosclerosis (GS) and atherosclerosis are thought to occur by similar pathogenic mechanisms. Central to this analogy between the atherosclerosis and GS processes is the origin and functional properties of the glomerular mesangial cell (MC). There are similarities between contractile glomerular MC and vascular smooth muscle cells. Hyperlipidaemia is believed to play a role in atherogenesis and the progression of renal disease. Much research in the past decade has focused on post-secretory modification of lipoproteins such as oxidation and their potential role in promoting atherosclerosis. This study investigated whether low density lipoproteins (LDL) are oxidatively modified by MC and if interaction of oxidatively modified LDL with MC may cause glomerular injury and potentially influence glomerulosclerosis. Our results demonstrate firstly that rat and human mesangial cells have the ability to oxidise LDL in vitro. The oxidative mechanism involves superoxide anions but other free radicals may also be involved. Experiments designed to compare LDL oxidation by MC with other cell types present in the kidney, such as endothelial cells, proximal tubular cells and monocyte/macrophages, demonstrated that endothelial cells oxidatively modified LDL to the greatest extent. Mesangial cells oxidised LDL to a similar extent to that of macrophages. Secondly, mesangial cells express scavenger type receptors that are capable of binding and internalising modified lipoproteins which may result in unregulated uptake of lipoproteins. Finally, exposure of oxidised LDL to mesangial cells caused a decrease in cell proliferation at low concentrations and cytotoxicity at higher concentrations. These results support the hypothesis that that the interaction of modified LDL with mesangial cells contributes to glomerular injury and may play a role the pathogenesis of glomerulosclerosis.

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