Cytokine regulation of low-density lipoprotein receptor gene transcription in human mesangial cells.

Abstract

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). We explored the effects of 50 ng/ml of tumour necrosis factor alpha (TNF alpha), 5 ng/ml of transforming growth factor beta (TGF beta), platelet-derived growth factor (PDGF), and interleukin-1beta (IL-1beta) 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. TNF alpha, TGF beta, PDGF or IL-1beta did not significantly stimulate HMCL proliferation at the concentrations given above, but maximally stimulated LDLr mRNA expression and increased LDLr promoter activity by 167.48+/-23.56%, 150.47+/-24.41%, 127.71+/-24.65% and 163.01+/-31.91% 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-1beta involved calmodulin, serine/threonine kinase and PKC pathways in upregulating LDLr. A high concentration of LDL (250 microg/ml) inhibited promoter activity, but TNF alpha, TGF beta, PDGF and IL-1beta co-incubated with LDL could override transcriptional inhibition by LDL. TNF alpha, TGF beta, PDGF and IL-1beta 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.