X Z Ruan1, Z Varghese, S H Powis, J F Moorhead. 1. Centre for Nephrology, Royal Free and University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, England, UK. xzruan@rfc.ucl.ac.uk
Abstract
BACKGROUND: Lipid-mediated renal injury is an important component of glomerulosclerosis and its similarity to atherosclerosis is well described. This study focused on the relationship between lipid-mediated injury and inflammation by examining the role of inflammatory cytokines in the regulation of human mesangial cell low-density lipoprotein (LDL) receptors. METHODS: A human mesangial cell line (HMCL) was used to study the effects of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) on the regulation of LDL receptor mRNA and protein in the presence of a high concentration of native LDL (250 microg/mL). RESULTS: Native LDL caused foam cell formation in HMCL in the presence of antioxidants, TNF-alpha and IL-1beta. Both cytokines overrode LDL receptor suppression induced by a high concentration of LDL and increased LDL uptake by enhancing receptor expression. These cytokines also caused increased expression of SCAP [sterol responsive element binding protein (SREBP) cleavage activation protein], and an increase in the nuclear translocation of SREBP, which induces LDL receptor expression. CONCLUSION: These observations demonstrate that inflammatory cytokines can modify cholesterol-mediated LDL receptor regulation in mesangial cells, permitting unregulated intracellular accumulation of unmodified LDL and causing foam cell formation. These findings suggest that inflammatory cytokines contribute to lipid-mediated renal damage, and also may have wider implications for the study of inflammation in the atherosclerotic process.
BACKGROUND:Lipid-mediated renal injury is an important component of glomerulosclerosis and its similarity to atherosclerosis is well described. This study focused on the relationship between lipid-mediated injury and inflammation by examining the role of inflammatory cytokines in the regulation of human mesangial cell low-density lipoprotein (LDL) receptors. METHODS: A human mesangial cell line (HMCL) was used to study the effects of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) on the regulation of LDL receptor mRNA and protein in the presence of a high concentration of native LDL (250 microg/mL). RESULTS: Native LDL caused foam cell formation in HMCL in the presence of antioxidants, TNF-alpha and IL-1beta. Both cytokines overrode LDL receptor suppression induced by a high concentration of LDL and increased LDL uptake by enhancing receptor expression. These cytokines also caused increased expression of SCAP [sterol responsive element binding protein (SREBP) cleavage activation protein], and an increase in the nuclear translocation of SREBP, which induces LDL receptor expression. CONCLUSION: These observations demonstrate that inflammatory cytokines can modify cholesterol-mediated LDL receptor regulation in mesangial cells, permitting unregulated intracellular accumulation of unmodified LDL and causing foam cell formation. These findings suggest that inflammatory cytokines contribute to lipid-mediated renal damage, and also may have wider implications for the study of inflammation in the atherosclerotic process.
Authors: Qiang Ye; Yaxi Chen; Han Lei; Qing Liu; John F Moorhead; Zac Varghese; Xiong Z Ruan Journal: Inflamm Res Date: 2009-06-17 Impact factor: 4.575
Authors: Amelia K Boehme; Niren Kapoor; Karen C Albright; Michael J Lyerly; Pawan V Rawal; Reza Bavarsad Shahripour; Muhammad Alvi; J Thomas Houston; April Sisson; T Mark Beasley; Anne W Alexandrov; Andrei V Alexandrov; David W Miller Journal: J Stroke Cerebrovasc Dis Date: 2014-01-11 Impact factor: 2.136