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A Novel Mechanism for 13‐cis Retinoic Acid mediated Angiotesin Type 1 Receptor Downregulation
Author(s) -
Snyder Russell Odell,
Thekkumkara Thomas
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.702.1
Subject(s) - downregulation and upregulation , retinoic acid , psychological repression , angiotensin ii , retinoic acid receptor , endocrinology , medicine , biology , chemistry , cancer research , biochemistry , receptor , gene , gene expression
Transcriptional repression through cis and trans acting factors enabling an alternate approach to control of angiotensin type 1 receptor (AT1R) dysfunction has not been studied. We hypothesized that in liver cells 13‐cis‐retinoic acid (13cRA), an antioxidant, by PPARγ; activation enhances insulin sensitive glucose mediated downregulation of the AT1R. In this study, we demonstrated that 13cRA treatment (25μM) downregulated the AT1R protein (40%) and mRNA (40%) in a dose and time dependent manner. However, the AT1R downregulation was independent of insulin sensitive glucose uptake. Reporter gene assays show that the promoter activity was inhibited by 13cRA. Sequence analysis revealed a region 2766 bp upstream of the start site similar to the retinoic acid response element in other genes. Studies using MAP‐Kinase inhibitor PD 98059 prevented 13cRA mediated AT1R downregulation. Furthermore, treatment of Trichostatin A reversed 13cRA mediated AT1R repression, suggesting that the catalytic and nuclear bioavailability of histone deacetylases may play a role in 13cRA induced AT1R repression. In summary, our results indicate for the first time that 13cRA has a glucose independent mechanism for transcriptional inhibition of AT1R. The observed effects by 13cRA suggest its therapeutic potential as an anti‐hypertensive agent in nondiabetic as well as diabetic hypertension. (Supported by NIH Grant DK072140)