Ruan, Xiong Zhong; (2001) Insights into regulation of lipoprotein receptors in human mesangial cells: The effects of inflammatory cytokines and calcium channel blockers. Doctoral thesis (Ph.D.), University College London.

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Abstract

The involvement of abnormal lipid metabolism in the progression of renal disease and the pathogenesis of chronic graft dysfunction is generally accepted. The dysregulation of lipoprotein homeostasis is involved in the incidence of accelerated cardiovascular disease in this population. Chronic renal dysfunction is also an inflammatory condition. Therefore, the present study was undertaken to investigate various mechanisms involved in the receptor-mediated regulation of intracellular lipoprotein transport and its interactions with inflammatory cytokines. Using human mesangial cell line (HMCL) culture, we demonstrated that HMCL express native LDL receptors. Phorbol 12-myristate 13-acetate (PMA), Angiotensin II (Ang II), TNF-α, and IL-1β induced acetylated-LDL internalisation, scavenger receptor mRNA expression and promoter activity. Both AP-1 and ets motifs were specific response elements to PMA-induced scavenger receptor expression. Conventionally, LDL receptor pathway is not thought to be involved in foam cells formation due to the tight metabolic control through a feedback regulation. However, our studies demonstrated that TNF-α, TGF-β, PDGF, or IL-1β increased LDL binding, LDL receptor mRNA expression and LDL receptor promoter activity. Both TNF-α, and IL-1β overrode the suppression of LDL receptor activity caused by a high concentration of native LDL and caused foam cell formation in HMCL. TNF-α, and IL-1β also increased the expression of a cleavage activating protein (SCAP) for sterol regulatory element binding proteins (SREBP). Diltiazem and verapamil, not nifedipine increased LDL binding, LDL receptor mRNA expression and LDL receptor promoter activity, but they were not able to override sterol-induced inhibition. Our results suggest that inflammatory cytokines may contribute to lipid deposition and foam cell formation in HMC through following pathways: 1) inducing scavenger receptor expression; 2) disregulating LDL receptor gene expression by increasing sterol-independent and mitogenesis-independent gene transcription. The implications of these findings are that inflammatory cytokines are important risk factors for glomerular atherosclerosis. Therefore, future strategies for controlling progression of renal and cardiovascular diseases should include anti-oxidants, lipid-lowering, and anti-inflammatory drugs.

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