Dietary potassium supplementation and sodium restriction stimulate aldosterone synthase but not 11 beta-hydroxylase P-450 messenger ribonucleic acid accumulation in rat adrenals and require angiotensin II production.

Abstract

Increasing evidence indicates that the adrenal cortex of most mammalian species expresses distinct forms of cytochrome P-450(11 beta), a steroidogenic enzyme that catalyses the terminal steps in the biosynthesis of both glucocorticoids and mineralocorticoids. In the human, mouse, and rat, two genes have been isolated, designated CYP11B1 and CYP11B2. The product of CYP11B2 (aldosterone synthase) is required for the successive 11 beta-, 18-hydroxylations and 18-oxidation of deoxycorticosterone that lead to the production of aldosterone in the zona glomerulosa. In contrast, the product of CYP11B1 (11 beta-hydroxylase) mediates only the 11 beta-hydroxylation of deoxycorticosterone and 11-deoxycortisol. The recent identification of these two P-450(11 beta) isozymes mandates further analysis of their expression in different zones of the adrenal cortex, both under basal conditions and in response to conditions known to alter mineralocorticoid biosynthesis. To evaluate the expression of the two isozymes in different adrenocortical zones, we performed Northern blotting analyses with specific oligonucleotide probes that discriminated between the two forms of rat P-450(11 beta). The transcripts detected by the two probes were of similar size (2.7 kilobase), but differed in their zonal distribution: aldosterone synthase P-450 messenger RNA (mRNA) was detected only in zona glomerulosa, whereas 11 beta-hydroxylase P-450 was expressed in both zona fasciculata-reticularis and zona glomerulosa. Next, we analyzed the response of these two genes to various physiological and pharmacological interventions known to affect aldosterone biosynthesis. High potassium or low sodium diet given to rats for 1 week increased aldosterone synthase P-450 mRNA levels by approximately 5- and 6-fold, respectively. These increases, moreover, were significantly attenuated by treatment with captopril, an inhibitor of angiotensin-converting enzyme. In contrast, neither dietary manipulation significantly affected 11 beta-hydroxylase P-450 mRNA levels in any zone. Thus, stimulation of the terminal steps of aldosterone biosynthesis by variations in dietary intake of monovalent cations involves regulation of aldosterone synthase P-450 mRNA levels. Finally, captopril inhibited potassium induction of aldosterone synthase P-450 mRNA levels despite the presence of low plasma renin activity in the potassium-treated rats. This finding implicates intraadrenal angiotensin II formation in the effect of potassium on mineralocorticoid production.

Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion.

“…15 years later, Boyd et al (21) documented some 0.5 mEq/liter increase in plasma potassium level during dietary salt restriction and speculated on an intermediary role of potassium in the secondary hyperaldosteronism. However, studies (1)(2)(3)22) have since demonstrated that the attempt to inhibit Ang II by a pharmacological measure is commonly effective in reversing the hyperaldosteronism, leading to the current prevailing notion that the role of potassium in this condition, if any, is channelled through the action of the renin-angiotensin system (23).…”

Renin knockout rat: control of adrenal aldosterone and corticosterone synthesis in vitro and adrenal gene expression

“…The second is that the local expression of adrenal renin is required for normal ZG function (7,9,10,14,16,26,28,29,31). One of the theories is that local generation of adrenal ANG II mediates the ZG response to increases in potassium and that this is mediated by AT 1 -type angiotensin receptors (14,26,29).…”

“…The classic renal renin-angiotensin-aldosterone system (RAAS) is well known as a major regulator of sodium and potassium balance. However, it has been known for decades that the adrenal cortex also expresses a local RAAS that operates independently of the renal RAAS (2,7,9,14,16,26,28). One theory is that adrenal renin-generated ANG II mediates the ZG response to increases in plasma potassium, and this is mediated by expression of the angiotensin AT 1 receptor (5,9,14,26,29).…”

“…However, it has been known for decades that the adrenal cortex also expresses a local RAAS that operates independently of the renal RAAS (2,7,9,14,16,26,28). One theory is that adrenal renin-generated ANG II mediates the ZG response to increases in plasma potassium, and this is mediated by expression of the angiotensin AT 1 receptor (5,9,14,26,29).The development of the renin knockout (KO) rat provides a unique opportunity to begin to evaluate these phenomena (13).In the current study, we have begun this process by evaluating the aldosterone and corticosterone response to cAMP in vitro by the measurement of adrenal steroidogenic gene expression and by morphological examination of adrenal zonation by immunohistochemical analysis of the two major late-pathway steroidogenic enzymes: P450aldo (CYP11B2) that mediates the conversion of corticosterone to aldosterone in the ZG and P45011␤ (CYP11B1) that mediates corticosterone production in the zona fasciculata/reticularis (ZFR) (8). …”

Potassium‐angiotensin interplay in the regulation of aldosterone biosynthesis

“…This fact was reinforced more recently by Tremblay et al (1992) who demonstrated that potassium supplementation or sodium restriction in rats increased aldosterone synthase but not 1 ID-hydroxylase P-450 mRNA. It should be noted that under both regimens angiotensin I1 was required, as captopril blocked these responses.…”