**2.1 Aldosterone biosynthesis**

Aldosterone is the main human mineralocorticoid. The main site of aldosterone synthesis is the zona glomerulosa (ZG) in the adrenal cortex. However, it can be produced by extra-adrenal tissues such as the central nervous system, the cardiovascular system, and the adipose tissue with a non-detectable physiological relevance and a small contribution to circulating aldosterone levels [1].

It is synthesized from cholesterol by a group of enzymatic cascade (**Figure 1**). First, cholesterol is translocated into the mitochondria across its wall mediated by steroidogenic acute regulatory protein (StAR). Cholesterol is then converted to pregnenolone, through three reactions, a 20α-hydroxylation, a 22-hydroxylation, and cleavage of the bond between C-20 and C-22 catalyzed by the *CYP11A1* cleavage enzyme, encoded by the *CYP11A1* gene on human chromosome 15 [2].

The produced pregnenolone is then released into the cytoplasm where it undergoes dehydrogenation of the 3β-hydroxyl group and isomerization of the double bond at C-5 to Δ4 by 3β-hydroxysteroid dehydrogenase (3β-HSD) and converted to progesterone [3]. Furthermore, progesterone undergoes 21-hydroxylation by the *CYP21A* enzyme encoded by *CYP21A* mapped to human chromosome 6p21·3 and located on the cytoplasmic surface of the smooth endoplasmic reticulum, generating 11-deoxycorticosterone (DOC). Then, DOC passes through three consecutive reactions catalyzed by aldosterone synthase enzyme, located on the inner mitochondrial membrane and encoded by the *CYP11B2* gene, 11β-hydroxylation to corticosterone, 18-hydroxylation to 18-hydroxycorticosterone, and finally 18-methyloxidation to aldosterone [4].

#### **2.2 Mechanism of action of aldosterone**

The action of aldosterone is mediated though mineralocorticoid receptor (MR), a specific nuclear receptor that comprises N-terminal domain, DNA-binding domain, and C-terminal ligand-binding domain. It is present as a hetero-oligomeric

**19**

**Figure 2.**

*Aldosterone Synthase Gene (*CYP11B2*) Polymorphisms and Enhanced Cardiovascular Risk*

complex with heat-shock proteins in the cell. Once aldosterone binds to its receptor, it undergoes a conformational change resulting in dissociation of the associated proteins, dimerization, and nuclear translocation [5]. This hormone receptor complex combines with the steroid responsive elements in the 5′-UTR of aldosterone-responsive genes with the release of aldosterone-induced proteins (AIP) that

The serine threonine glucocorticoid regulated kinase 1 (sgk1), which is one of the AIP proteins, has been phosphorylated and activated by the aldosterone, which in turn phosphorylates epithelial sodium channel (ENaC) regulatory protein, known as Nedd4–2, reducing its binding to ENaC [6] with subsequent increase in ENaC density and stability at the apical membrane resulting in increased ENaC-

and the corticosteroid hormone-induced factor (CHIF) are also AIP proteins. GILZ interacts with aldosterone inhibiting the ERK signaling pathway, thus liberating ENaC from Nedd4 proteins; accordingly, its action in blocking sodium reabsorption is inhibited [8]. CHIF may affect the baso-lateral Na/K-pump, resulting in increased sodium reabsorption with potassium or hydrogen ion excretion (**Figure 2**) [9]. Aldosterone also exerts a genomic action via modulating the gene expression and subsequent protein production that result in a lag time of 1–2 h before a noticeable

As the kidneys are the main site of action for aldosterone, MRs are confined mainly in high concentration to the renal distal convoluted tubules and collecting duct controlling the apically located epithelial sodium channels at their luminal cells. Mineralocorticoid receptors also exist in other epithelial sites, such as the colon, sweat gland ducts, salivary glands [11], and non-epithelial sites including

*Mechanism of action of aldosterone in epithelial cells. Abbreviations: ENaC, epithelial sodium channel; HRE, hormone response element; GILZ, glucocorticoid-induced leucine zipper protein; Nedd4-2, neuronal precursor cell-expressed, developmentally down-regulated protein; Sgk1, serine threonine glucocorticoid regulated kinase* 

*1; CHIF, channel-inducing factor; MR, mineralocorticoid receptor.*

reabsorption [7]. The glucocorticoid-induced leucine zipper (GILZ)

*DOI: http://dx.doi.org/10.5772/intechopen.89133*

enhances or suppresses gene transcription [4].

change in target cell activity occur [10].

**2.3 Physiological action of aldosterone**

dependent Na+

#### **Figure 1.**

*Enzymatic cascade of the aldosterone biosynthesis.*

*Aldosterone Synthase Gene (*CYP11B2*) Polymorphisms and Enhanced Cardiovascular Risk DOI: http://dx.doi.org/10.5772/intechopen.89133*

complex with heat-shock proteins in the cell. Once aldosterone binds to its receptor, it undergoes a conformational change resulting in dissociation of the associated proteins, dimerization, and nuclear translocation [5]. This hormone receptor complex combines with the steroid responsive elements in the 5′-UTR of aldosterone-responsive genes with the release of aldosterone-induced proteins (AIP) that enhances or suppresses gene transcription [4].

The serine threonine glucocorticoid regulated kinase 1 (sgk1), which is one of the AIP proteins, has been phosphorylated and activated by the aldosterone, which in turn phosphorylates epithelial sodium channel (ENaC) regulatory protein, known as Nedd4–2, reducing its binding to ENaC [6] with subsequent increase in ENaC density and stability at the apical membrane resulting in increased ENaCdependent Na+ reabsorption [7]. The glucocorticoid-induced leucine zipper (GILZ) and the corticosteroid hormone-induced factor (CHIF) are also AIP proteins. GILZ interacts with aldosterone inhibiting the ERK signaling pathway, thus liberating ENaC from Nedd4 proteins; accordingly, its action in blocking sodium reabsorption is inhibited [8]. CHIF may affect the baso-lateral Na/K-pump, resulting in increased sodium reabsorption with potassium or hydrogen ion excretion (**Figure 2**) [9]. Aldosterone also exerts a genomic action via modulating the gene expression and subsequent protein production that result in a lag time of 1–2 h before a noticeable change in target cell activity occur [10].

## **2.3 Physiological action of aldosterone**

As the kidneys are the main site of action for aldosterone, MRs are confined mainly in high concentration to the renal distal convoluted tubules and collecting duct controlling the apically located epithelial sodium channels at their luminal cells. Mineralocorticoid receptors also exist in other epithelial sites, such as the colon, sweat gland ducts, salivary glands [11], and non-epithelial sites including

#### **Figure 2.**

*The Recent Topics in Genetic Polymorphisms*

Aldosterone is the main human mineralocorticoid. The main site of aldosterone synthesis is the zona glomerulosa (ZG) in the adrenal cortex. However, it can be produced by extra-adrenal tissues such as the central nervous system, the cardiovascular system, and the adipose tissue with a non-detectable physiological

The produced pregnenolone is then released into the cytoplasm where it undergoes dehydrogenation of the 3β-hydroxyl group and isomerization of the double bond at C-5 to Δ4 by 3β-hydroxysteroid dehydrogenase (3β-HSD) and converted to progesterone [3]. Furthermore, progesterone undergoes 21-hydroxylation by the *CYP21A* enzyme encoded by *CYP21A* mapped to human chromosome 6p21·3 and located on the cytoplasmic surface of the smooth endoplasmic reticulum, generating 11-deoxycorticosterone (DOC). Then, DOC passes through three consecutive reactions catalyzed by aldosterone synthase enzyme, located on the inner mitochondrial membrane and encoded by the *CYP11B2* gene, 11β-hydroxylation to corticosterone, 18-hydroxylation to 18-hydroxycorticosterone, and finally

The action of aldosterone is mediated though mineralocorticoid receptor (MR),

a specific nuclear receptor that comprises N-terminal domain, DNA-binding domain, and C-terminal ligand-binding domain. It is present as a hetero-oligomeric

relevance and a small contribution to circulating aldosterone levels [1]. It is synthesized from cholesterol by a group of enzymatic cascade (**Figure 1**). First, cholesterol is translocated into the mitochondria across its wall mediated by steroidogenic acute regulatory protein (StAR). Cholesterol is then converted to pregnenolone, through three reactions, a 20α-hydroxylation, a 22-hydroxylation, and cleavage of the bond between C-20 and C-22 catalyzed by the *CYP11A1* cleavage enzyme, encoded by the *CYP11A1* gene on human

**2.1 Aldosterone biosynthesis**

**2. Aldosterone**

chromosome 15 [2].

18-methyloxidation to aldosterone [4].

*Enzymatic cascade of the aldosterone biosynthesis.*

**2.2 Mechanism of action of aldosterone**

**18**

**Figure 1.**

*Mechanism of action of aldosterone in epithelial cells. Abbreviations: ENaC, epithelial sodium channel; HRE, hormone response element; GILZ, glucocorticoid-induced leucine zipper protein; Nedd4-2, neuronal precursor cell-expressed, developmentally down-regulated protein; Sgk1, serine threonine glucocorticoid regulated kinase 1; CHIF, channel-inducing factor; MR, mineralocorticoid receptor.*

myocytes, endocardium of the heart, brain, vascular smooth muscle, liver, and leukocytes [12]. The main action of aldosterone is stimulation of sodium reabsorption in the kidney and at other secretory epithelial sites with excretion of potassium and hydrogen ions [13] possibly mediated via increasing the opening periods of the existing ion channels or increasing their number [14].

In cardiovascular system, aldosterone promotes myocardial hypertrophy and fibrosis via increasing collagen I synthesis in cardiac fibroblasts and also elevating endothelin receptor numbers that further increases collagen synthesis [15]. So, increased expression of mineralocorticoid receptors in the heart may result in left-ventricular hypertrophy in normotensive subjects [16]. Aldosterone also stimulates vascular constriction via enhancing the pressor response to catecholamines and impairing the vasodilatory response to acetylcholine or by upregulation of angiotensin II receptors [4]. Also, aldosterone excess can trigger collagen deposition in blood vessels, enhancing vascular remodeling and reducing compliance [17]. In the CNS, it appears to regulate blood pressure, salt appetite, and sympathetic tone [4].

Under normal circumstances, it is likely that cardiac MRs are occupied by glucocorticoid due to its higher circulating concentration exerting antagonistic effect attenuating the rise in blood pressure and the cardiac fibrosis caused by aldosterone alone [18].
