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2017 ; 7
(9
): 1410-1421
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High glucose stimulates expression of aldosterone synthase (CYP11B2) and
secretion of aldosterone in human adrenal cells
#MMPMID28904869
Shimada H
; Kogure N
; Noro E
; Kudo M
; Sugawara K
; Sato I
; Shimizu K
; Kobayashi M
; Suzuki D
; Parvin R
; Saito-Ito T
; Uruno A
; Saito-Hakoda A
; Rainey WE
; Ito S
; Yokoyama A
; Sugawara A
FEBS Open Bio
2017[Sep]; 7
(9
): 1410-1421
PMID28904869
show ga
Aldosterone synthase is the key rate-limiting enzyme in adrenal aldosterone
production, and induction of its gene (CYP11B2) 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 CYP11B2 expression and
aldosterone production using human adrenal H295R cells and a stable H295R cell
line expressing a CYP11B2 5'-flanking region/luciferase cDNA chimeric construct.
d-glucose (d-glu), but not its enantiomer l-glucose, dose dependently induced
CYP11B2 transcription and mRNA expression. A high concentration (450 mg·dL(-1))
of d-glu time dependently induced CYP11B2 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 CYP11B2 5'-flanking
region revealed that the NBRE-1 element, known to be activated by transcription
factors NGFIB and NURR1, was responsible for the high glucose-mediated effect.
High glucose also induced the mRNA expression of these transcription factors,
especially that of NURR1, but NURR1 knockdown using its siRNA did not affect high
glucose-induced CYP11B2 mRNA expression. Taken together, it is speculated that
high glucose may induce CYP11B2 transcription via the NBRE-1 element in its
5'-flanking region, resulting in the increase in aldosterone production although
high glucose-induced NURR1 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.