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1,25-Dihydroxyvitamin D3 targeting of NF-kappaB suppresses high glucose-induced MCP-1 expression in mesangial cells

Z Zhang1, W Yuan, L Sun

  • 1Department of Medicine and Committee on Molecular Metabolism and Nutrition, Division of Biological Sciences, The University of Chicago, Chicago, Illinois 60637, USA.

Kidney International
|May 18, 2007
PubMed

Insights

Vitamin D (1,25(OH)2D3) blocks high glucose-induced kidney injury by inhibiting monocyte chemoattractant protein-1 (MCP-1) production via the NF-kappaB pathway. This suggests a potential therapeutic role for vitamin D in diabetic nephropathy.

Area of Science:

  • Nephrology
  • Endocrinology
  • Molecular Biology

Background:

  • Diabetic nephropathy is characterized by macrophage infiltration in the kidneys, driven by monocyte chemoattractant protein-1 (MCP-1).
  • Vitamin D and its analogs possess renoprotective properties, but their specific role in diabetic nephropathy requires further elucidation.

Purpose of the Study:

  • To investigate the mechanisms by which 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) exerts renoprotective effects in diabetic nephropathy.
  • To assess the impact of 1,25(OH)2D3 on MCP-1 expression and NF-kappaB activation in mesangial cells (MCs).

Main Methods:

  • Utilized luciferase reporter assays to measure MCP-1 transcription in response to high glucose and 1,25(OH)2D3.
  • Employed electrophoretic mobility shift and chromatin immunoprecipitation assays to analyze NF-kappaB binding and p65/p50 activity.
  • Investigated the effect of 1,25(OH)2D3 on IkappaBalpha stabilization and p65 translocation.
  • Examined MCP-1 levels in primary MCs from vitamin D receptor knockout mice.
  • Evaluated the efficacy of paricalcitol in a mouse model of diabetic nephropathy.

Main Results:

  • High glucose significantly increased MCP-1 transcription, an effect inhibited by 1,25(OH)2D3.
  • High glucose enhanced p65/p50 binding to NF-kappaB sites, which was suppressed by 1,25(OH)2D3.
  • 1,25(OH)2D3 stabilized IkappaBalpha, inhibiting p65 nuclear translocation and NF-kappaB binding.
  • Vitamin D receptor knockout MCs showed elevated basal MCP-1 levels, unaffected by 1,25(OH)2D3.
  • Paricalcitol reduced MCP-1 induction and activity, ameliorating glomerulosclerosis in diabetic mice.

Conclusions:

  • 1,25-dihydroxyvitamin D3 inhibits high glucose-induced MCP-1 production in MCs by suppressing NF-kappaB activation.
  • Vitamin D receptor signaling is crucial for the inhibitory effects of 1,25(OH)2D3 on MCP-1.
  • These findings suggest that 1,25(OH)2D3 and its analogs may represent a therapeutic strategy for mitigating hyperglycemia-induced renal injury in diabetic nephropathy.

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