Open AccessHigh glucose stimulates expression of aldosterone synthase ( CYP 11B2 ) and secretion of aldosterone in human adrenal cells
Author(s) -
Shimada Hiroki,
Kogure Naotaka,
Noro Erika,
Kudo Masataka,
Sugawara Kaori,
Sato Ikuko,
Shimizu Kyoko,
Kobayashi Makoto,
Suzuki Dai,
Parvin Rehana,
SaitoIto Takako,
Uruno Akira,
SaitoHakoda Akiko,
Rainey William E.,
Ito Sadayoshi,
Yokoyama Atsushi,
Sugawara Akira
Publication year - 2017
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1002/2211-5463.12277
Subject(s) - aldosterone , aldosterone synthase , gene knockdown , medicine , endocrinology , biology , messenger rna , gene expression , transcription (linguistics) , transfection , downregulation and upregulation , gene , renin–angiotensin system , biochemistry , blood pressure , linguistics , philosophy
Aldosterone synthase is the key rate‐limiting enzyme in adrenal aldosterone production, and induction of its gene ( CYP 11B2 ) results in the progression of hypertension. As hypertension is a frequent complication among patients with diabetes, we set out to elucidate the link between diabetes mellitus and hypertension. We examined the effects of high glucose on CYP 11B2 expression and aldosterone production using human adrenal H295R cells and a stable H295R cell line expressing a CYP 11B2 5′‐flanking region/luciferase cDNA chimeric construct. d ‐glucose ( d ‐glu), but not its enantiomer l ‐glucose, dose dependently induced CYP 11B2 transcription and mRNA expression. A high concentration (450 mg·dL −1 ) of d ‐glu time dependently induced CYP 11B2 transcription and mRNA expression. Moreover, high glucose stimulated secretion of aldosterone into the media. Transient transfection studies using deletion mutants/nerve growth factor‐induced clone B (NGFIB) response element 1 ( NBRE ‐1) point mutant of CYP 11B2 5′‐flanking region revealed that the NBRE ‐1 element, known to be activated by transcription factors NGFIB and NURR 1, was responsible for the high glucose‐mediated effect. High glucose also induced the mRNA expression of these transcription factors, especially that of NURR 1, but NURR 1 knockdown using its si RNA did not affect high glucose‐induced CYP 11B2 mRNA expression. Taken together, it is speculated that high glucose may induce CYP 11B2 transcription via the NBRE ‐1 element in its 5′‐flanking region, resulting in the increase in aldosterone production although high glucose‐induced NURR 1 is not directly involved in the effect. Additionally, glucose metabolism and calcium channels were found to be involved in the high glucose effect. Our observations suggest one possible explanation for the high incidence of hypertension in patients with diabetes.