1,25-Dihydroxyvitamin D 3 suppresses high glucose-induced angiotensinogen expression in kidney cells by blocking the NF-κB pathway

• Published in: American journal of physiology. Renal physiology Vol. 296; no. 5; pp. F1212 - F1218
• Main Authors: Deb, Dilip K., Chen, Yunzi, Zhang, Zhongyi, Zhang, Yan, Szeto, Frances L., Wong, Kari E., Kong, Juan, Li, Yan Chun
• Format: Journal Article
• Language: English
• Published: 01.05.2009
• DOI: 10.1152/ajprenal.00002.2009
• ISSN: 1931-857X

The renin-angiotensin system (RAS) is a major mediator of renal injury in diabetic nephropathy. Our previous studies demonstrated that 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] plays a renoprotective role by suppressing the RAS, with renin and angiotensinogen (AGT) as the main targets. The mechanism whereby 1,25(OH) 2 D 3 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) 2 D 3 (20 nM) or NF-κB inhibitor BAY 11–7082, suggesting the involvement of NF- κB in HG-induced AGT expression and the interaction between 1,25(OH) 2 D 3 and NF-κB in the regulation. Plasmid pNF-κB-Luc luciferase reporter assays showed that 1,25(OH) 2 D 3 blocked HG-induced NF-κB activity. EMSA and ChIP assays demonstrated increased p65/p50 binding to a NF-κB binding site at −1734 in the AGT gene promoter upon high glucose stimulation, and the binding was disrupted by 1,25(OH) 2 D 3 treatment. Overexpression of p65/p50 overcame 1,25(OH) 2 D 3 suppression, and mutation of this NF-κB binding site blunted 1,25(OH) 2 D 3 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) 2 D 3 suppresses hyperglycemia-induced AGT expression by blocking NF-κB-mediated pathway.