- Email: [email protected]
Aldosterone
SUBCHAPTER 95E
Aldosterone Yoshinao Katsu and Taisen Iguchi
Abbreviation: A or ALDO Additional names: 11β,21-dihydroxypregn-4-ene-3,18,20trione; 18-aldocorticosterone; 11β,21-dihydroxy-3,20-dioxo-4pregnen-18-al; Reichstein X Aldosterone is a steroid hormone produced by the adrenal cortex in the adrenal gland to regulate sodium and potassium balance in the blood. It specifically regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. It is synthesized from cholesterol by aldosterone (ALDO) synthase in the zona glomerulosa of the adrenal gland. Aldosterone is the principal mammalian mineralocorticoid.
Discovery Simpson and Tait (1953) developed a bioassay with high sensitivity for mineralocorticoid activity, and crystallized ALDO (electrocortin) from beef adrenal glands.
Properties Mr 360.44. Melting point: 166.5 C. Water solubility: 0.0512 mg/ml. Experimental solubility: soluble in ethanol, chloroform, glycols, vegetable oils, acetone, ether, and methanol. Insoluble in water.
Synthesis and Release Gene, mRNA, and Precursor The human CYP11B2 gene, located on chromosome 8 (8q21 q22), consists of nine exons. Human CYP11B2 mRNA has 2,935 bp that encode a protein of 503 aa residues (E-Figures 95E.1 and 95E.2, and E-Table 95E.1).
Tissue and Plasma Concentration Reference values are 50 800 pg/ml for children (standing), 30 350 pg/ml for children (lying down), 70 300 pg/ml for adults (standing), and 30 160 pg/ml for adults (lying down) [4].
Structure Structural Features
Regulation of Synthesis and Release
By 1954 the structure of ALDO had been reported (Figure 95E.1) [1]. ALDO is produced from 18hydroxycorticosterone by ALDO synthase (CYP11B) activity. The production of ALDO is regulated at the two critical enzyme steps: (1) in its biosynthetic pathway (the conversion of cholesterol to pregnenolone by cholesterol side chain cleavage enzyme) and (2) the conversion of corticosterone to ALDO by ALDO synthase. Steroidogenic acute regulatory protein (StAR) controls the transport of cholesterol to the inner mitochondrial membrane where P450scc (CYP11A1) is located. CYP11A1 converts cholesterol to pregnenolone. Pregnenolone can be modified to deoxycorticosterone by two enzyme activities 3β-hydroxysteroid dehydrogenase (3β-HSD) and 21-hydroxylase at the smooth endoplasmic reticulum. Deoxycorticosterone is converted to corticosterone by 11β-hydroxylase at the mitochondria in the zona fasciculata of the adrenal gland. In the zona glomerulosa of the adrenal gland, corticosterone is modified to 18hydroxycorticosterone and then to ALDO. This synthetic cascade is regulated by ALDO synthase, CYP11B2 [2]. This ALDO synthase is absent in other sections of the adrenal gland, and the teleost fishes probably lack ALDO synthase CYP11B2, suggesting that the dominant corticosteroid is cortisol [3].
A variety of factors modify ALDO secretion, such as the levels of pituitary adrenocorticotropic hormone (ACTH) and kidney angiotensin II, and the plasma concentration of potassium ions. ACTH acts as an enhancer of StAR synthesis via the activation of cAMP-dependent protein kinase A. Angiotensin II, which is converted from angiotensin I by angiotensinconverting enzyme, is involved in the regulation of ALDO [5]. Angiotensin II stimulates synthesis and release of ALDO from zona glomerulosa (renin angiotensin system). High levels of serum potassium directly stimulate aldosterone secretion from the zona glomerulosa. An increase in dietary potassium induces an increase in ALDO secretion whereas potassium depletion causes a decrease. Some animal studies show the physiological function for potassium is the regulation of ALDO secretion [5]. Thus, alterations in potassium balance as well as acute increments in serum potassium can stimulate the production of ALDO [6]. On the other hand, atrial natriuretic peptide (ANP) is an inhibitory factor of ALDO secretion. ANP secretion is increased in response to sodium and/or water loading, and it in turn inhibits ALDO secretion [7]. In human, the dosage of ANP induces the reduction of plasma renin and ALDO concentrations and inhibits angiotensin II-induced ALDO secretion.
Y. Takei, H. Ando, & K. Tsutsui (Eds): Handbook of Hormones. DOI: http://dx.doi.org/10.1016/B978-0-12-801028-0.00232-4 © 2016 Elsevier Inc. All rights reserved.
535
P A R T I I I Lipophilic Hormones in Vertebrates O HO
HC=O
OH
OH
O Figure 95E.1 Structure of ALDO.
Biological Functions
Pathophysiological Implications Clinical Implications Hyperaldosteronism is characterized by low blood potassium and high blood sodium. Elevated plasma sodium levels bring about water retention and may produce hypertension. Primary hyperaldosteronism is induced by the overproduction of ALDO by the adrenal gland; secondary hyperaldosteronism is due to overactivity of the renin angiotensin system. Treatment with ALDO inhibitors can reduce these symptoms until the source of the excessive ALDO is removed. Hypoaldosteronism induces a reduction of potassium excretion. Further water retention is impaired, and sodium is lost in the urine.
Physiological Actions
Use for Diagnosis and Treatment
ALDO achieves its physiological effects by controlling the transcription of specific genes attached to the mineralocorticoid receptor (MR) in the target cell. ALDO has the most powerful mineralocorticoid activity, corresponding to controlling sodium homeostasis. ALDO regulates the transcription of the epithelial sodium channel and Na1/K1-ATPase subunit genes. Consequently, ALDO promotes the reabsorption of sodium from renal tubules. Thus, ALDO is a critical regulator of serum sodium and electrolytes [6].
The concentrations of serum aldosterone are routinely measured in the diagnosis of many diseases associated with hyperaldosteronism and hypoaldosteronism. Aldosterone itself is not used for clinical treatment. Fludrocortisone, a synthetic mineralocorticoid, is administered to some patients in relation to mineralocorticoid deficiency.
Mechanisms of Actions ALDO achieves the typical steroidal pattern of action on target cells after binding to the cytoplasmic receptor, MR. This mechanism is called “genomic action” of ALDO. The ALDOMR complex binds to a specific hormone response element located at the gene promoter region, and leads to its gene specific transcription. Human MR consists of 984 amino acids, and has 57% amino acid identity with the human glucocorticoid receptor (GR) in the ligand-binding domain, and 94% in the DNA-binding domain. The non-genomic pathway as well as the genomic pathway also affects the ALDO mediated biological function at the cellular level via the non-classical receptor, MR. This non-genomic pathway, less well characterized to date, involves numerous signaling pathways in kidney, colon, vascular wall, and heart [8].
536
References 1. Simpson SA, Tait JF, Wettstein A, et al. Aldosteron. Isolierung und ¨ ber Bestandteile der Nebennierenrinde und verEigenschaften. U wandte Stoffe. 91. Mitteilung. Helv Chim Acta. 1954;37:1163 1200. 2. Lisurek M, Bernhardt R. Modulation of aldosterone and cortisol synthesis on the molecular level. Mol Cell Endocrinol. 2004;215:149 159. 3. Bury NR, Sturm A. Evolution of the corticosteroid receptor signaling pathway in fish. Gen Comp Endocrinol. 2007;153:47 56. 4. Fischbach FT, Dunning III MB, eds. Manual of Laboratory and Diagnostic Tests. 8th ed. Philadelphia: Lippincott Williams and Wilkins; 2009. 5. Stocco DM, Clark BJ. The role of the steroidogenic acute regulatory protein in steroidogenesis. Steroids. 1997;62:29 36. 6. Amasheh S, Epple HJ, Mankertz J, et al. Differential regulation of EnaC by aldosterone in rat early and late distal colon. Ann NY Acad Sci. 2000;915:92 94. 7. Spa¨t A, Hunyady L. Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol Rev. 2004; 84:489 539. 8. Funder JW. The nongenomic actions of aldosterone. Endocrine Rev. 2005;26:313 321.
S U B C H A P T E R 9 5 E Aldosterone Supplemental Information
E-Figure 95E.1 Human CYP11B2 precursor: location 8q21-q22. UTR, untranslated region; CDS, coding sequences.
e95E-1
P A R T I I I Lipophilic Hormones in Vertebrates
E-Figure 95E.2 The alignment of amino acid sequences of CYP11B2 in mammals. Accession numbers: human (Homo sapiens), NP_000489; rat (Rattus norvegicus), NP_036670; mouse (Mus musculus), NP_034121; dog (Canis lupus familiaris), XP_539192; monkey (Macaca mulatta), NM_001193748; guinea pig (Cavia porcellus, NP_001166566.
E-Table 95E.1 Accession Numbers of Gene and cDNA for CYP11B2 Species
Gene
cDNA
Human Mouse Rat Dog Monkey Guinea pig
NG_008374 NC_000081 NC_005106 NC_006595 NC_007865 NT_176324
NM_000498 NM_009991 NM_012538 XM_539192 NP_001180677 NM_001173095
e95E-2
Aldosterone Yoshinao Katsu and Taisen Iguchi
Abbreviation: A or ALDO Additional names: 11β,21-dihydroxypregn-4-ene-3,18,20trione; 18-aldocorticosterone; 11β,21-dihydroxy-3,20-dioxo-4pregnen-18-al; Reichstein X Aldosterone is a steroid hormone produced by the adrenal cortex in the adrenal gland to regulate sodium and potassium balance in the blood. It specifically regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. It is synthesized from cholesterol by aldosterone (ALDO) synthase in the zona glomerulosa of the adrenal gland. Aldosterone is the principal mammalian mineralocorticoid.
Discovery Simpson and Tait (1953) developed a bioassay with high sensitivity for mineralocorticoid activity, and crystallized ALDO (electrocortin) from beef adrenal glands.
Properties Mr 360.44. Melting point: 166.5 C. Water solubility: 0.0512 mg/ml. Experimental solubility: soluble in ethanol, chloroform, glycols, vegetable oils, acetone, ether, and methanol. Insoluble in water.
Synthesis and Release Gene, mRNA, and Precursor The human CYP11B2 gene, located on chromosome 8 (8q21 q22), consists of nine exons. Human CYP11B2 mRNA has 2,935 bp that encode a protein of 503 aa residues (E-Figures 95E.1 and 95E.2, and E-Table 95E.1).
Tissue and Plasma Concentration Reference values are 50 800 pg/ml for children (standing), 30 350 pg/ml for children (lying down), 70 300 pg/ml for adults (standing), and 30 160 pg/ml for adults (lying down) [4].
Structure Structural Features
Regulation of Synthesis and Release
By 1954 the structure of ALDO had been reported (Figure 95E.1) [1]. ALDO is produced from 18hydroxycorticosterone by ALDO synthase (CYP11B) activity. The production of ALDO is regulated at the two critical enzyme steps: (1) in its biosynthetic pathway (the conversion of cholesterol to pregnenolone by cholesterol side chain cleavage enzyme) and (2) the conversion of corticosterone to ALDO by ALDO synthase. Steroidogenic acute regulatory protein (StAR) controls the transport of cholesterol to the inner mitochondrial membrane where P450scc (CYP11A1) is located. CYP11A1 converts cholesterol to pregnenolone. Pregnenolone can be modified to deoxycorticosterone by two enzyme activities 3β-hydroxysteroid dehydrogenase (3β-HSD) and 21-hydroxylase at the smooth endoplasmic reticulum. Deoxycorticosterone is converted to corticosterone by 11β-hydroxylase at the mitochondria in the zona fasciculata of the adrenal gland. In the zona glomerulosa of the adrenal gland, corticosterone is modified to 18hydroxycorticosterone and then to ALDO. This synthetic cascade is regulated by ALDO synthase, CYP11B2 [2]. This ALDO synthase is absent in other sections of the adrenal gland, and the teleost fishes probably lack ALDO synthase CYP11B2, suggesting that the dominant corticosteroid is cortisol [3].
A variety of factors modify ALDO secretion, such as the levels of pituitary adrenocorticotropic hormone (ACTH) and kidney angiotensin II, and the plasma concentration of potassium ions. ACTH acts as an enhancer of StAR synthesis via the activation of cAMP-dependent protein kinase A. Angiotensin II, which is converted from angiotensin I by angiotensinconverting enzyme, is involved in the regulation of ALDO [5]. Angiotensin II stimulates synthesis and release of ALDO from zona glomerulosa (renin angiotensin system). High levels of serum potassium directly stimulate aldosterone secretion from the zona glomerulosa. An increase in dietary potassium induces an increase in ALDO secretion whereas potassium depletion causes a decrease. Some animal studies show the physiological function for potassium is the regulation of ALDO secretion [5]. Thus, alterations in potassium balance as well as acute increments in serum potassium can stimulate the production of ALDO [6]. On the other hand, atrial natriuretic peptide (ANP) is an inhibitory factor of ALDO secretion. ANP secretion is increased in response to sodium and/or water loading, and it in turn inhibits ALDO secretion [7]. In human, the dosage of ANP induces the reduction of plasma renin and ALDO concentrations and inhibits angiotensin II-induced ALDO secretion.
Y. Takei, H. Ando, & K. Tsutsui (Eds): Handbook of Hormones. DOI: http://dx.doi.org/10.1016/B978-0-12-801028-0.00232-4 © 2016 Elsevier Inc. All rights reserved.
535
P A R T I I I Lipophilic Hormones in Vertebrates O HO
HC=O
OH
OH
O Figure 95E.1 Structure of ALDO.
Biological Functions
Pathophysiological Implications Clinical Implications Hyperaldosteronism is characterized by low blood potassium and high blood sodium. Elevated plasma sodium levels bring about water retention and may produce hypertension. Primary hyperaldosteronism is induced by the overproduction of ALDO by the adrenal gland; secondary hyperaldosteronism is due to overactivity of the renin angiotensin system. Treatment with ALDO inhibitors can reduce these symptoms until the source of the excessive ALDO is removed. Hypoaldosteronism induces a reduction of potassium excretion. Further water retention is impaired, and sodium is lost in the urine.
Physiological Actions
Use for Diagnosis and Treatment
ALDO achieves its physiological effects by controlling the transcription of specific genes attached to the mineralocorticoid receptor (MR) in the target cell. ALDO has the most powerful mineralocorticoid activity, corresponding to controlling sodium homeostasis. ALDO regulates the transcription of the epithelial sodium channel and Na1/K1-ATPase subunit genes. Consequently, ALDO promotes the reabsorption of sodium from renal tubules. Thus, ALDO is a critical regulator of serum sodium and electrolytes [6].
The concentrations of serum aldosterone are routinely measured in the diagnosis of many diseases associated with hyperaldosteronism and hypoaldosteronism. Aldosterone itself is not used for clinical treatment. Fludrocortisone, a synthetic mineralocorticoid, is administered to some patients in relation to mineralocorticoid deficiency.
Mechanisms of Actions ALDO achieves the typical steroidal pattern of action on target cells after binding to the cytoplasmic receptor, MR. This mechanism is called “genomic action” of ALDO. The ALDOMR complex binds to a specific hormone response element located at the gene promoter region, and leads to its gene specific transcription. Human MR consists of 984 amino acids, and has 57% amino acid identity with the human glucocorticoid receptor (GR) in the ligand-binding domain, and 94% in the DNA-binding domain. The non-genomic pathway as well as the genomic pathway also affects the ALDO mediated biological function at the cellular level via the non-classical receptor, MR. This non-genomic pathway, less well characterized to date, involves numerous signaling pathways in kidney, colon, vascular wall, and heart [8].
536
References 1. Simpson SA, Tait JF, Wettstein A, et al. Aldosteron. Isolierung und ¨ ber Bestandteile der Nebennierenrinde und verEigenschaften. U wandte Stoffe. 91. Mitteilung. Helv Chim Acta. 1954;37:1163 1200. 2. Lisurek M, Bernhardt R. Modulation of aldosterone and cortisol synthesis on the molecular level. Mol Cell Endocrinol. 2004;215:149 159. 3. Bury NR, Sturm A. Evolution of the corticosteroid receptor signaling pathway in fish. Gen Comp Endocrinol. 2007;153:47 56. 4. Fischbach FT, Dunning III MB, eds. Manual of Laboratory and Diagnostic Tests. 8th ed. Philadelphia: Lippincott Williams and Wilkins; 2009. 5. Stocco DM, Clark BJ. The role of the steroidogenic acute regulatory protein in steroidogenesis. Steroids. 1997;62:29 36. 6. Amasheh S, Epple HJ, Mankertz J, et al. Differential regulation of EnaC by aldosterone in rat early and late distal colon. Ann NY Acad Sci. 2000;915:92 94. 7. Spa¨t A, Hunyady L. Control of aldosterone secretion: a model for convergence in cellular signaling pathways. Physiol Rev. 2004; 84:489 539. 8. Funder JW. The nongenomic actions of aldosterone. Endocrine Rev. 2005;26:313 321.
S U B C H A P T E R 9 5 E Aldosterone Supplemental Information
E-Figure 95E.1 Human CYP11B2 precursor: location 8q21-q22. UTR, untranslated region; CDS, coding sequences.
e95E-1
P A R T I I I Lipophilic Hormones in Vertebrates
E-Figure 95E.2 The alignment of amino acid sequences of CYP11B2 in mammals. Accession numbers: human (Homo sapiens), NP_000489; rat (Rattus norvegicus), NP_036670; mouse (Mus musculus), NP_034121; dog (Canis lupus familiaris), XP_539192; monkey (Macaca mulatta), NM_001193748; guinea pig (Cavia porcellus, NP_001166566.
E-Table 95E.1 Accession Numbers of Gene and cDNA for CYP11B2 Species
Gene
cDNA
Human Mouse Rat Dog Monkey Guinea pig
NG_008374 NC_000081 NC_005106 NC_006595 NC_007865 NT_176324
NM_000498 NM_009991 NM_012538 XM_539192 NP_001180677 NM_001173095
e95E-2