Biphasic Time Course of the Changes in Aldosterone Biosynthesis Under High-Salt Conditions in Dahl Salt-Sensitive Rats

Abstract

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. In Dahl-S rats, we found that the delayed and paradoxical increase in aldosterone biosynthesis after the initial and appropriate response to high salt. The late rise in aldosterone biosynthesis was accompanied by upregulation of CYP11B2 expression in the zona glomerulosa and increased adrenal angiotensin II levels and renin-angiotensin system components. It preceded the appearance of left ventricular systolic dysfunction and renal insufficiency. Blockade of angiotensin AT 1 receptors reversed the paradoxical increase in aldosterone biosynthesis. In contrast, Dahl-R rats maintained the initial suppression of aldosterone biosynthesis. Aldosterone levels in the heart closely paralleled those in the plasma and adrenal gland and disappeared after bilateral adrenalectomy. Conclusion-Chronic salt overload in Dahl-S rats stimulates aberrant aldosterone production via activation of the local renin-angiotensin system in the adrenal gland, thereby creating the comorbidity of excess salt and elevated plasma aldosterone. (Arterioscler Thromb Vasc Biol . 2012;32:1194-1203 .)

Renin‐Angiotensin‐Aldosterone System, Glucose Metabolism and Incident Type 2 Diabetes Mellitus: MESA

“…There are many plausible mechanisms including salt‐sensitivity, production of aldosterone, receptor binding, and post‐receptor signal transduction in response to aldosterone. In the Dahl Salt‐Sensitive rat, aldosterone is suppressed acutely in response to salt loads, but aldosterone becomes paradoxically elevated over time 19. Inappropriate RAAS activation, combined with the maladaptive inability to lower aldosterone levels in response to high salt intake constitute a major issue in all ethnicities, but may be especially relevant in populations with higher levels of salt‐sensitivity including individuals of Chinese and African ancestry 20, 21.…”

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

“…The first is that adequate, chronic concentrations of circulating plasma ANG II are required for the normal development and expression of aldosterone synthase activity in the rat adrenal. This is supported by studies showing a decrease in aldosterone production and P450aldo expression with decreased stimulation of the adrenal gland by circulating plasma ANG II (8,14,15,17). Values are means of cycles to threshold (CT) Ϯ SE (N ϭ 6 samples per experimental group).…”

“…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).…”

“…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). …”

“…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).…”