Nephrology Dialysis Transplantation, Vol 13, Issue 6 1391-1397, Copyright © 1998 by Oxford University Press
X Ruan, Z Varghese, R Fernando and J Moorhead
Background: The intracellular transport of lipids
through regulation of the LDL receptor (LDLr) may be important in the
progression of renal dysfunction. The present study was undertaken to
investigate whether cytokines have any major effects on LDLr regulation and
lipid-mediated glomerular injury in human mesangial cells (HMC).
Methods: We explored the effects of 50 ng/ml of tumour
necrosis factor &agr; (TNF&agr;), 5 ng/ml of transforming growth
factor {beta} (TGF{beta}), platelet-derived growth factor (PDGF), and
interleukin-1{beta} (IL-1{beta}) on the regulation of LDLr gene
transcription in a human mesangial cell line (HMCL) using cell
proliferation, LDL binding, northern blot and LDLr promoter activity
assays. Results: TNF&agr;, TGF{beta}, PDGF or
IL-1{beta} did not significantly stimulate HMCL proliferation at the
concentrations given above, but maximally stimulated LDLr mRNA expression
and increased LDL promoter activity by 167.48±23.56%,
150.47±24.41%, 127.71±24.65% and
163.01±31.9% respectively, at 24 h. An increased LDL binding was
observed in parallel with increased LDLr mRNA. The tyrosine kinase
transduction pathway was involved in LDLr upregulation induced by all four
cytokines. Additionally, TGF{beta} involved serine/threonine kinase and
G-protein pathways, and IL-1{beta} involved calmodulin, serine/threonine
kinase and PKC pathways in upregulating LDLr. A high concentration of LDL
(250 &mgr;g/ml) inhibited promoter activity, but TNF&agr;,
TGF{beta}, PDGF and IL-1{beta} co-incubated with LDL could override
transcriptional inhibition by LDL. Conclusion:
TNF&agr;, TGF{beta}, PDGF and IL-1{beta} increased LDLr gene
expression by increasing sterol-independent and mitogenesis-independent
gene transcription. This process may contribute to lipid deposition and
foam cell formation in HMC. Key words: cytokine;
glomerulosclerosis; gene transcription; human mesangial cell; LDL receptor;
LDL receptor gene promoter
ORIGINAL ARTICLES
Cytokines regulation of low-density lipoprotein receptor gene transcription in human mesangial cells
Renal Research Unit, Royal Free Hospital School of Medicine, London NW3 2QG, UK; Corresponding author
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