Acute and chronic regulation of aldosterone production

Abstract

Aldosterone is the major mineralocorticoid synthesized by the adrenal and plays an important role in the regulation of systemic blood pressure through the absorption of sodium and water. Aldosterone production is regulated tightly by selective expression of aldosterone synthase (CYP11B2) in the adrenal outermost zone, the zona glomerulosa. Angiotensin II (Ang II), potassium (K(+)) and adrenocorticotropin (ACTH) are the main physiological agonists which regulate aldosterone secretion. Aldosterone production is regulated within minutes of stimulation (acutely) through increased expression and phosphorylation of the steroidogenic acute regulatory (StAR) protein and over hours to days (chronically) by increased expression of the enzymes involved in the synthesis of aldosterone, particularly CYP11B2. Imbalance in any of these processes may lead to several disorders of aldosterone excess. In this review we attempt to summarize the key molecular events involved in the acute and chronic phases of aldosterone secretion.

Figure 1. Adrenocortical steroidogenic pathways for the production of mineralocorticoids and glucocorticoids

The adrenal cortex produces zone-specific steroids as a result of differential expression of steroidogenic enzymes. In the initial step of steroidogenesis, steroidogenic acute regulatory (StAR) protein is needed for the rate-limiting step of movement of cholesterol to the inner mitochondrial membrane, where cholesterol is cleaved by cholesterol side-chain cleavage (CYP11A1) to pregnenolone. Further steps of the steroidogenic pathway include the enzymes 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2), 17α-hydroxylase, 17,20-lyase (CYP17), 21-hydrolylase (CYP21), 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2).

Figure 2. Acute actions of AngII, K⁺ and ACTH on adrenal glomerulosa cell aldosterone production

AngII binds the AT₁ receptor to activate phosphoinositide-specific phospholipase C (PLC)-mediated cleavage of phosphatidylinositol 4,5-bisphosphate (PIP₂) to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP₃). IP₃ binds the IP₃R on the endoplasmic reticulum (ER), releasing calcium and raising cytosolic calcium concentrations. AngII also activates, in part through protein kinase C (PKC), phospholipase D (PLD), which hydrolyzes phosphatidylcholine (PC) to phosphatidic acid (PA) which can be metabolized to DAG by lipid phosphate phosphatases. Small increases in extracellular K⁺ depolarize the glomerulosa cell, activating the voltage-operated L- and T-type calcium channels, increasing calcium influx. Increased intracellular calcium concentration activates calcium/calmodulin-dependent protein kinases I/II (CaMK), as well as PKC isoforms. Both of these pathways can modulate not only StAR phosphorylation, but also expression, likely in part through the StAR promoter binding of cAMP response element binding protein (CREB). The DAG/PKC pathway also activates protein kinase D (PKD) which can likewise phosphorylate (and activate) CREB. DAG can be hydrolyzed by DAG lipase to release arachidonic acid, which can be further metabolized by 12-lipoxygenase to 12-hydroxyeicosatetraenoic acid (12-HETE), which also induces the phosphorylation (and activation) of CREB. ACTH can also mediate aldosterone synthesis through binding to the melanocortin type 2 receptor (MC2R), thus activating through a heterotrimeric G_s protein, adenylate cyclase (AC). AC converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). cAMP activates protein kinase A (PKA) inducing a slow but sustained calcium influx through the L-type calcium channels. PKA also phosphorylates CREB, thereby increasing StAR expression. Cholesterol for aldosterone production arises from cholesteryl ester hydrolase (CEH)-mediated hydrolysis of cholesteryl esters synthesized de novo or obtained from lipoproteins and stored in lipid droplets. Free cholesterol is shuttled to the inner mitochondrial membrane by StAR likely in complex with other cholesterol transport proteins.

Figure 3. The chronic production of aldosterone is regulated by AngII and potassium (K⁺)

AngII binds type 1 AngII receptors (AT₁-R) and activates phospholipase C (PLC) which causes hydrolysis of phosphatidylinositol-4,5-bisphosphate to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP₃). DAG activates protein kinase C (PKC) which inhibits transcription of 17α-hydrolyase (CYP17) through transcription factors such as cFOS. DAG may also increase the activity of protein kinase D (PKD), which has been shown to increase CYP11B2 transcription. IP₃ causes the release of intracellular calcium and the activation of calcium-calmodulin kinases (CaMKs). Small increases in extracellular K⁺ also depolarize the glomerulosa cell, increasing calcium influx and activating CaMKs. CaMKs increase expression and/or phosphorylation and activation of transcription factors that increase CYP11B2 transcription. Further, binding of Ang II to the AT₁-R also increases the expression of LDL and HDL receptors, which increases cholesterol availability for steroidogenesis.