1,25-Dihydroxyvitamin D3 targeting of NF-κB 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 D-3 (1,25(OH)(2)D-3) 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)(2)D-3. Electrophoretic mobility shift and chromatin immunoprecipitation assays showed that HG increased the p65/p50 binding to the two NF-kappa B sites within the promoter. This was suppressed by 1,25(OH)(2)D-3, but this decrease was reversed by overexpression of p65. 1,25(OH)(2)D-3 was found to stabilize IjBa leading to an inhibition of p65 translocation to the nucleus and subsequent reduction of NF-kappa B binding. In primary MCs prepared from vitamin D receptor knockout animals, basal MCP-1 levels were elevated but not affected by 1,25(OH)(2)D-3. 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)(2)D-3 might block hyperglycemia- induced renal injury by blunting NF-kappa B activation.