CYP11B2
Cytochrome P450 11B2, mitochondrial precursor (Aldosterone synthase) (ALDOS) (Aldosterone-synthesizing enzyme) (CYPXIB2) (Corticosterone 18-monooxygenase, CYP11B2) (EC 1.14.15.5) (Cytochrome P-450Aldo) (Cytochrome P-450C18) (Steroid 11-beta-hydroxylase, CYP11B2) (EC 1.14.15.4) (Steroid 18-hydroxylase)
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Immunohistochemistry of human aldosterone synthase (CYP11B2) has revealed that most of aldosterone is autonomously produced in aldosterone-producing cell clusters (APCCs) beneath the capsule of adult adrenals rather than physiologically in the zona glomerulosa (ZG). APCCs have been occasionally found to harbor a somatic mutation of ion channel/pump genes, and number and size of APCCs increase with age until 50 years old. Herein, the objective of the study was to examine APCC development in 106 autopsied adrenals from 85 elderly individuals who died at ages from 50 to 103 years. We obtained the following results: (1) physiological CYP11B2 expression in ZG were attenuated in more elderly persons; (2) number and size of APCCs decreased with age; (3) detachment of APCC from the capsule appeared to occur occasionally over the wide range of the ages; and (4) incidental micro aldosterone-producing adenomas (APAs) and possible APCC-to-APA transitional lesions (pAATLs) were found primarily in samples from persons aged 50-60 years but not in samples from more elderly persons; pAATL was a putative designation based on our previous results indicating that it consisted of subcapsular APCC-like portion and inner APA-like portions. Thus, the formation of the CYP11B2-expressing lesions as well as thickening of the ZG in the adrenals were inversely correlated with age of death in the individuals aged over 50 years. Considering that autopsy samples were used in this study, inactive production of aldosterone regardless of autonomous or physiological manners may have survival advantages in individuals aged over 50 years.
MeSH Terms
- Adrenal Glands
- Aged
- Aged, 80 and over
- Aging
- Aldosterone
- Cytochrome P-450 CYP11B2
- Female
- Humans
- Longevity
- Male
- Middle Aged
Keywords
- Adrenal gland
- Aldosterone synthase (CYP11B2)
- Aldosterone-producing adenoma (APA)
- Aldosterone-producing cell cluster (APCC)
Both aging and inappropriate secretion of aldosterone increase the risk for developing cardiovascular disease; however, the influence of aging on aldosterone secretion and physiology is not well understood. The relationship between age and adrenal aldosterone synthase (CYP11B2) expression was evaluated in 127 normal adrenal glands from deceased kidney donors (age, 9 months to 68 years). Following immunohistochemistry, CYP11B2-expressing area and areas of abnormal foci of CYP11B2-expressing cells, called aldosterone-producing cell clusters, were analyzed. In a separate ancillary clinical study of 677 participants without primary aldosteronism, who were studied on both high and restricted sodium diets (age, 18-71 years), we used multivariable linear regression to assess the independent associations between age and renin-angiotensin-aldosterone system physiology. In adrenal tissue, the total CYP11B2-expressing area was negatively correlated with age ([i]r[/i]=-0.431, [i]P[/i]<0.0001), whereas the total aldosterone-producing cell cluster area was positively correlated with age ([i]r[/i]=0.390, [i]P[/i]<0.0001). The integrated ratio of aldosterone-producing cell cluster to CYP11B2-expressing area was most strongly and positively correlated with age ([i]r[/i]=0.587, [i]P[/i]<0.0001). When participants in the clinical study were maintained on a high sodium balance, renin activity progressively declined with older age, whereas serum and urinary aldosterone did not significantly decline. Correspondingly, the aldosterone-to-renin ratio was positively and independently associated with older age (adjusted β= 5.54 ng/dL per ng/mL per hour per 10 years, [i]P[/i]<0.001). In contrast, when participants were assessed under sodium-restricted conditions, physiological stimulation of aldosterone was blunted with older age (β=-4.6 ng/dL per 10 years, [i]P[/i]<0.0001). Aging is associated with a pattern of decreased normal zona glomerulosa CYP11B2 expression and increased aldosterone-producing cell cluster expression. This histopathologic finding parallels an age-related autonomous aldosteronism and abnormal aldosterone physiology that provides 1 potential explanation for age-related cardiovascular risk.
MeSH Terms
- Adolescent
- Adrenal Glands
- Adult
- Age Factors
- Aged
- Aging
- Child
- Child, Preschool
- Cytochrome P-450 CYP11B2
- Female
- Humans
- Hyperaldosteronism
- Infant
- Male
- Middle Aged
- Young Adult
Keywords
- aging
- aldosterone
- aldosterone-producing cell cluster
- cytochrome P-450 CYP11B2
- primary aldosteronism
- renin
Sonic hedgehog signaling was recently demonstrated to play an important role in murine adrenal cortex development. The organization of the rat adrenal differs from that of the mouse, with the zona glomerulosa and zona fasciculata separated by an undifferentiated zone in the rat, but not in the mouse. In the present study we aimed to determine the mRNA expression patterns of Sonic hedgehog and the hedgehog signaling pathway components Patched-1 and Gli1 in the developing and adult rat adrenal. Sonic hedgehog expression was detected at the periphery of the cortex in cells lacking CYP11B1 and CYP11B2 expression, while signal-receiving cells were localized in the overlying capsule mesenchyme. Using combined in situ hybridization and immunohistochemistry we found that the cells expressing Sonic hedgehog lie between the CYP11B2 and CYP11B1 layers, and thus Sonic hedgehog expression defines one cell population of the undifferentiated zone.
MeSH Terms
- Adrenal Cortex
- Aging
- Animals
- Gene Expression Regulation, Developmental
- Hedgehog Proteins
- Kruppel-Like Transcription Factors
- Mice
- Patched Receptors
- Patched-1 Receptor
- Protein Transport
- Rats
- Receptors, Cell Surface
- Zinc Finger Protein GLI1
Aldosterone participates in vascular and myocardial inflammation either directly or indirectly through blood pressure (BP). Aldosterone synthase (CYP11B2) C-344T polymorphism may influence the severity of systemic inflammation. A total of 398 Japanese Americans (152 men and 246 women, age 19-92 years) from the Hawaii-Los Angeles-Hiroshima study were enrolled. BP and serum levels of C-reactive protein (CRP) were measured, and the CYP11B2 C-344T polymorphism, rs1799998, was determined. No influence of the polymorphism on baseline characteristics such as systolic, diastolic and mean BP, pulse pressure or serum CRP levels was observed. In all genotypes, systolic BP showed a significantly positive correlation with age (TT (n=178): r=0.283, P<0.001; TC (n=164): r=0.213, P=0.006; and CC (n=56): r=0.289, P=0.031). However, the regression coefficients of systolic BP with age were not different across genotypes. According to the results of univariate and multivariate analyses with adjustment for BP, the serum CRP level increased with age only in subjects with the CC genotype (P=0.027 and P=0.004, respectively), and elevation of serum CRP was mainly observed in the elderly population (aged >or=60 years). Moreover, the regression coefficient of CRP levels with age was significantly steeper in subjects with the CC genotype than in those with the TC or TT genotype (P=0.028). The CC genotype of the CYP11B2 C-344T polymorphism was associated with an age-dependent increase in the serum CRP level independent of BP, and may contribute to a cardiovascular phenotype by promoting vascular inflammation.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Atherosclerosis
- Blood Pressure
- C-Reactive Protein
- Cytochrome P-450 CYP11B2
- Female
- Genetic Predisposition to Disease
- Genotype
- Humans
- Hypertension
- Japan
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Young Adult
To study the interaction between the C(-344)T polymorphism and known determinants (age, body mass and dietary sodium) of blood pressure and plasma aldosterone. Cross-sectional and longitudinal (1980-1995) survey of male workers in southern Italy. Medical centre of the Olivetti factories. In 1995, the C(-344)T polymorphism was characterized in 811 untreated men. A subgroup of 280 participants already seen in 1980 was the object of longitudinal analysis. Blood pressure, demographic, anthropometric and biochemical variables (serum and urinary electrolytes and plasma aldosterone) and frequency of the C(-344)T polymorphism. In the whole population, there was no difference among genotypes for any of the variables examined. However, multiple regression showed a significant interaction between age (but not body mass or sodium intake) and genotype with regard to systolic (P = 0.03) and diastolic ( P= 0.02) pressure variability independently of covariates. Diastolic pressure increased linearly with age in carriers of the T allele (TT, P<0.001 and TC, P= 0.005), but not in CC homozygotes ( P= 0.848). In T carriers - but not in CC homozygotes - blood pressure and serum potassium increased and plasma aldosterone and serum sodium decreased across quintiles of age (P< 0.001 for all trends). In the longitudinal study, diastolic pressure increased significantly over time only in T carriers (TC TT: 2.6 /- 0.6, versus CC: -0.4 /- 1.5 mmHg, P= 0.04). Inter-individual variation of blood pressure and plasma aldosterone is affected by the interaction of C(-344)T polymorphism and ageing, thus supporting a role for this variant in mechanisms affecting blood pressure regulation.
MeSH Terms
- Aging
- Aldosterone
- Blood Pressure
- Cross-Sectional Studies
- Cytochrome P-450 CYP11B2
- Diastole
- Follow-Up Studies
- Genotype
- Heterozygote
- Humans
- Longitudinal Studies
- Male
- Middle Aged
- Phenotype
- Polymorphism, Genetic
- Potassium
The three zones of adrenal cortex are thought to arise from a single multipotential stem cell. Immunohistochemical studies of fetal and adult adrenals using an antibody against a previously-cloned ZOG protein, a rat homolog of Pref-1, were conducted to explore its roles in the differentiation of cortical tissues. At the early embryonic stage, ZOG was already expressed in adrenogonadal primordial cells. The ZOG-positive cells gradually formed the adrenal primordium by E14.5. By E17.5 the expression was repressed in the inner part of the aggregate and these cells began to express CYP11B1. The ZOG-positive cells at this stage existed at the periphery of the aggregate but they did not express CYP11B2 yet. Not until E20.5 did the aldosteronogenic cells appear among the ZOG-positive cells at the outermost part of the gland. Based on these and the other findings the zonal development of the adrenal cortex is discussed.
MeSH Terms
- Adrenal Cortex
- Aging
- Aldosterone
- Animals
- Antigens
- DNA-Binding Proteins
- Embryonic and Fetal Development
- Fetus
- Fushi Tarazu Transcription Factors
- Homeodomain Proteins
- Immunohistochemistry
- Intercellular Signaling Peptides and Proteins
- Membrane Proteins
- Rats
- Receptors, Cytoplasmic and Nuclear
- Steroid 11-beta-Hydroxylase
- Steroidogenic Factor 1
- Transcription Factors
- Zona Reticularis