1,25-Dihydroxyvitamin D3 targeting of NF-kappaB suppresses high glucose-induced MCP-1 expression in mesangial cells.
Macrophages accumulate in kidney glomeruli and interstitium of patients with diabetic nephropathy in response to monocyte chemoattractant protein-1 (MCP-1); a chemokine produced by both tubular epithelial and mesangial cells (MCs). Vitamin D and its analogs have been shown to have renoprotective effects; however, there are few studies involving diabetic nephropathy. We explored mechanisms by which 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) can be renoprotective by measuring MCP-1 expression in MCs. Using a luciferase reporter assay, we found that high glucose (HG)-induced MCP-1 transcription and that this induction is blocked by 1,25(OH)2D3. Electrophoretic mobility shift and chromatin immunoprecipitation assays showed that HG increased the p65/p50 binding to the two NF-kappaB sites within the promoter. This was suppressed by 1,25(OH)2D3, but this decrease was reversed by overexpression of p65. 1,25(OH)2D3 was found to stabilize IkappaBalpha leading to an inhibition of p65 translocation to the nucleus and subsequent reduction of NF-kappaB binding. In primary MCs prepared from vitamin D receptor knockout animals, basal MCP-1 levels were elevated but not affected by 1,25(OH)2D3. The analog paricalcitol inhibited the induction and activity of MCP-1 while ameliorating glomerulosclerosis in streptozotocin-diabetic mice. Our results suggest that 1,25(OH)2D3 might block hyperglycemia-induced renal injury by blunting NF-kappaB activation.
Zhang
Z
Z
Department of Medicine and Committee on Molecular Metabolism and Nutrition, Division of Biological Sciences, The University of Chicago, Chicago, Illinois 60637, USA.
Yuan
W
W
Sun
L
L
Szeto
F L
FL
Wong
K E
KE
Li
X
X
Kong
J
J
Li
Y C
YC
D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental; D005947:Glucose / Q000494:pharmacology*; D050527:Mesangial Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000187:drug effects*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D018167:Receptors, Calcitriol; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
D018932:Chemokine CCL2; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D018167:Receptors, Calcitriol; D051996:Transcription Factor RelA; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D005947:Glucose