Adrenal cortex hypoxia modulates aldosterone production in heart failure.

Plasma aldosterone concentration increases in proportion to the severity of heart failure, even during treatment with renin-angiotensin system inhibitors. This study investigated alternative regulatory mechanisms of aldosterone production that are significant in heart failure. Dahl salt-sensitive rats on a high-salt diet, a rat model of heart failure with cardio-renal syndrome, had high plasma aldosterone levels and elevated β3-adrenergic receptor expression in hypoxic zona glomerulosa cells.

Human Adrenocortical Remodeling Leading to Aldosterone-Producing Cell Cluster Generation.

. The immunohistochemical detection of aldosterone synthase (CYP11B2) and steroid 11-hydroxylase (CYP11B1) has enabled the identification of aldosterone-producing cell clusters (APCCs) in the subcapsular portion of the human adult adrenal cortex. We hypothesized that adrenals have layered zonation in early postnatal stages and are remodeled to possess APCCs over time.

Functional zonation of the rat adrenal cortex: the development and maintenance.

The adrenal cortex of mammals consists of three concentric zones, i.e., the zona glomerulosa (zG), the zona fasciculata (zF), and the zona reticularis (zR), which secrete mineralocorticoids, glucocorticoids, and adrenal androgens, respectively.

Biphasic time course of the changes in aldosterone biosynthesis under high-salt conditions in Dahl salt-sensitive rats.

Objective: The comorbidity of excess salt and elevated plasma aldosterone has deleterious effects in cardiovascular disease. We evaluated the mechanisms behind the paradoxical increase in aldosterone biosynthesis in relation to dietary intake of salt.

Methods And Results: Dahl salt-sensitive (Dahl-S) and salt-resistant (Dahl-R) rats were fed a high-salt diet, and plasma and tissue levels of aldosterone in the adrenal gland and heart were quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry.

Corneal damage and lacrimal gland dysfunction in a smoking rat model.

Smoking is a serious public health problem around the world and causes many diseases such as chronic obstructive pulmonary disease, lung cancer, and some eye diseases. Cytochrome P450s (CYPs) are xenobiotic-metabolizing enzymes and are distributed in the corneas, protecting the ocular surface against chemical compounds in the environment. Although CYPs are principally detoxification enzymes, CYP1A1 and CYP2A6 are known to participate in the induction of lung cancer by smoking.

Adrenocortical zonation in humans under normal and pathological conditions.

Context: Aldosterone synthase (CYP11B2) and steroid 11 beta-hydroxylase (CYP11B1) catalyze the terminal steps for aldosterone and cortisol syntheses, respectively, thereby determining the functional differentiation of human adrenocortical cells. Little is known, however, about how the cells expressing the enzymes are actually distributed in the adrenals under normal and pathological conditions.

Objective: The objective of the study was to determine the localization of CYP11B2 and -B1 in human adrenal specimens by using developed antibodies capable of distinguishing the two enzymes from each other.

Cytochrome P-450(17alpha) in beta-cells of rat pancreas and its local steroidogenesis.

We have found cytochrome P-450(17alpha) in the islets of Langerhans of rat pancreas. Its existence coincided with that of insulin and demarcated those of glucagon and somatostatin, demonstrating the localization in beta-cells. The enzyme has not only 17alpha-hydroxylase activity but also lyase one, which is a prerequisite for androgen biosynthesis.

Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis.

ACTH (i.e., corticotropin) is the principal regulator of the hypothalamus-pituitary-adrenal axis and stimulates steroidogenesis in the adrenal gland via the specific cell-surface melanocortin 2 receptor (MC2R).

Adrenocortical zonation factor 1 is a novel matricellular protein promoting integrin-mediated adhesion of adrenocortical and vascular smooth muscle cells.

Expression of a previously cloned secretory protein named adrenocortical zonation factor 1 (AZ-1, also called Tin-ag-RP or lipocalin 7) is tightly linked with the zonal differentiation of adrenocortical cells. It is also present in vascular smooth muscle (VSM), although its function has remained unknown. In this study, the location of AZ-1 was specified to the basal laminae along adrenocortical sinusoidal capillaries and surrounding VSM cells in the arterial system, consistent with the fact that AZ-1 was extractable under denaturing conditions as a 52 kDa polypeptide.

Ascorbate stimulates monooxygenase-dependent steroidogenesis in adrenal zona glomerulosa.

It is well known that ascorbic acid (Asc) is highly concentrated in the adrenal gland, but its function in the gland is not thoroughly elucidated. We therefore examined the possibility that Asc participates in steroidogenic monooxygenase systems of the adrenal cortex with the aid of the regenerating system including outer mitochondrial membrane cytochrome b (OMb). When Asc availability was limited in rat mutants unable to synthesize Asc, the increase in plasma aldosterone concentration under Na-deficiency was suppressed without effect on plasma corticosterone concentration.

Gonadotropin stimuli increase adrenodoxin immunoreactivity in the mitochondria of rat ovarian cells.

Adrenodoxin is a component of the electron transfer system for mitochondrial cytochrome P450 in steroidogenic cells. To elucidate whether the steroidogenic state can modulate the amount and the distribution of adrenodoxin in the mitochondria, we determined immunohistochemically the distribution of adrenodoxin and 3beta-hydroxysteroid dehydrogenase (3betaHSD) in ovaries of rats under hypo- and hyperfunctional states. In the ovaries of control rats, adrenodoxin was distributed in the cristae of round-shaped mitochondria of both interstitial and theca cells.

Possible participation of outer mitochondrial membrane cytonchrome B5 in steroidogenesis in zona glomerulosa of rat adrenal cortex.

Outer mitochondrial membrane cytochrome b5 (OMb) originally found in rat liver is an isoform of cytochrome b5 (b5) of the endoplasmic reticulum. In contrast to accumulated data on the physiological roles of b5, functions of OMb have not been well characterized except for its involvement in regeneration of ascorbic acid [i.e.

Identification of outer mitochondrial membrane cytochrome b5 as a modulator for androgen synthesis in Leydig cells.

Outer mitochondrial membrane cytochrome b5 is an isoform of microsomal membrane cytochrome b5. In rat testes the outer mitochondrial membrane cytochrome b5 is present in both mitochondria and microsomes, whereas microsomal membrane cytochrome b5 is undetectable. Outer mitochondrial membrane cytochrome b5 present in the testis was localized in Leydig cells with cytochrome P-45017alpha, which catalyzes androgenesis therein.

An inverse correlation between expression of a preprocathepsin B-related protein with cysteine-rich sequences and steroid 11beta -hydroxylase in adrenocortical cells.

A cDNA encoding a secretory protein hitherto unknown was cloned from mouse adrenocortical cells by subtractive hybridization between the cells without and with expressing steroid 11beta-hydroxylase (Cyp11b-1), a marker for the functional differentiation of cells in the zonae fasciculata reticularis (zFR). The deduced protein consisting of 466 amino acids contained a secretory signal, epidermal growth factor-like repeats, and a proteolytically inactive cathepsin B-related sequence. The amino acid sequence was 89% identical with that of human tubulointerstitial nephritis antigen-related protein.

The undifferentiated cell zone is a stem cell zone in adult rat adrenal cortex.

The adrenal cortex of mammals has been known to consist of three morphologically and functionally distinct zones, i.e. the zona glomerulosa (zG), the zona fasciculata (zF) and the zona reticularis (zR), each of which secretes a specific corticosteroid different from those produced by the other two zones.

Conditionally immortalized adrenocortical cell lines at undifferentiated states exhibit inducible expression of glucocorticoid-synthesizing genes.

To facilitate studies on differentiation of adrenocortical cells and regulation of steroidogenic genes, we established cell lines from adrenals of adult transgenic mice harboring a temperature-sensitive large T-antigen gene of simian virus 40. Adrenal glands of the mice exhibited normal cortical zonation including a functionally undifferentiated cell-layer between the aldosterone-synthesizing zona glomerulosa cells and the corticosterone-synthesizing zona fasciculata cells. At a permissive temperature (33 degrees C), established cell lines AcA201, AcE60 and AcA101 expressed steroidogenic genes encoding steroidogenic factor-1, cholesterol side-chain cleavage P450scc, and steroidogenic acute regulatory protein, which are expressed throughout adrenal cortices and gonads.