Journal
KIDNEY INTERNATIONAL
Volume 72, Issue 2, Pages 193-201Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/sj.ki.5002296
Keywords
diabetic nephropathy; mesangial cells; monocyte chemoattractant protein-1; NF-kappa B; vitamin D; vitamin D receptor
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Funding
- NIDDK NIH HHS [DK59327, DK73183] Funding Source: Medline
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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.
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