kn-93 and olmesartan

We generated a stable H295R cell line expressing aldosterone synthase gene (CYP11B2) promoter/luciferase chimeric reporter construct that is highly sensitive to angiotensin II (AII) and potassium, and defined AII receptor blocker (ARB) effects. In the presence of AII, all ARBs suppressed AII-induced CYP11B2 transcription. However, telmisartan alone increased CYP11B2 transcription in the absence of AII. Telmisartan dose-dependently increased CYP11B2 transcription/mRNA expression and aldosterone secretion. Experiments using CYP11B2 promoter mutants indicated that the Ad5 element was responsible. Among transcription factors involved in the element, telmisartan significantly induced NGFIB/NURR1 expression. KN-93, a CaMK inhibitor, abrogated the telmisartan-mediated increase of CYP11B2 transcription/mRNA expression and NURR1 mRNA expression, but not NGFIB mRNA expression. NURR1 over-expression significantly augmented the telmisartan-mediated CYP11B2 transcription, while high-dose olmesartan did not affect it. Taken together, telmisartan may stimulate CYP11B2 transcription via NGFIB and the CaMK-mediated induction of NURR1 that activates the Ad5 element, independent of AII type 1 receptor.

Topics: Adrenal Glands; Aldosterone; Angiotensin Receptor Antagonists; Benzimidazoles; Benzoates; Benzylamines; Calcium-Calmodulin-Dependent Protein Kinases; Cell Line; Cytochrome P-450 CYP11B2; Gene Expression Regulation; Genes, Reporter; Humans; Imidazoles; Luciferases; Nuclear Receptor Subfamily 4, Group A, Member 1; Promoter Regions, Genetic; Protein Kinase Inhibitors; Receptors, Angiotensin; Sulfonamides; Telmisartan; Tetrazoles; Transcription, Genetic