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1,25-Dihydroxyvitamin D₃ suppresses high glucose-induced angiotensinogen expression in kidney cells by blocking the NF-B pathway

Department of Medicine and Committee on Molecular Metabolism and Nutrition, Division of Biological Sciences, The University of Chicago, Chicago, Illinois

Submitted 2 January 2009 ; accepted in final form 1 February 2009

The renin-angiotensin system (RAS) is a major mediator of renal injury in diabetic nephropathy. Our previous studies demonstrated that 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] plays a renoprotective role by suppressing the RAS, with renin and angiotensinogen (AGT) as the main targets. The mechanism whereby 1,25(OH)₂D₃ transcriptionally suppresses renin gene expression has been elucidated; however, how vitamin D regulates AGT remains unknown. Exposure of mesangial cells or podocytes to high glucose (HG; 30 mM) markedly stimulated AGT expression. In mesangial cells, the stimulation was inhibited by 1,25(OH)₂D₃ (20 nM) or NF-B inhibitor BAY 11–7082, suggesting the involvement of NF- B in HG-induced AGT expression and the interaction between 1,25(OH)₂D₃ and NF-B in the regulation. Plasmid pNF-B-Luc luciferase reporter assays showed that 1,25(OH)₂D₃ blocked HG-induced NF-B activity. EMSA and ChIP assays demonstrated increased p65/p50 binding to a NF-B binding site at –1734 in the AGT gene promoter upon high glucose stimulation, and the binding was disrupted by 1,25(OH)₂D₃ treatment. Overexpression of p65/p50 overcame 1,25(OH)₂D₃ suppression, and mutation of this NF-B binding site blunted 1,25(OH)₂D₃ suppression of the promoter activity. In mice lacking the vitamin D receptor, AGT mRNA expression in the kidney was markedly increased compared with wild-type mice, and AGT induction in diabetic mice was suppressed by treatment with a vitamin D analog. These data indicate that 1,25(OH)₂D₃ suppresses hyperglycemia-induced AGT expression by blocking NF-B-mediated pathway.

vitamin D receptor; renin-angiotensin system; diabetic nephropathy

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