aldosterone deficiency and resistance

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Aldosterone Deficiency and ResistanceKeiko Arai, M.D.Arai Clinic, Address: 1-19 Moegino, Aoba-ku, Yokohama 227-0044, Japan

George P Chrousos, MD, MACE, MACP, FRCPDivision of Endocrinology, Metabolism and Diabetes (N.C.N., G.P.C., E.C.), First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, ‘AghiaSophia’ Children's Hospital, Athens, 11527, Greece; Division of Endocrinology and Metabolism (N.C.N., G.P.C., E.C.), Center of Clinical, Experimental Surgery and TranslationalResearch, Biomedical Research Foundation of the Academy of Athens, Athens, 11527, Greece

Last Update: May 11, 2016.

ABSTRACTAldosterone is crucial for sodium conservation in the kidney, salivary glands, sweat glands and colon. Aldosterone promotes activesodium transport and excretion of potassium via the mineralocorticoid receptor (MR) and the resultant activation of specific amiloride-sensitive sodium channels (ENaC) and the Na-K ATP ase pump in the target tissues. Defective aldosterone action results in varioussymptoms and laboratory characteristics such as hyponatremia, hyperkalemia, acidosis, and so on. Primary adrenal insufficiency andcongenital adrenal hypoplasia are discussed in other chapters, In this chapter the mechanisms underlying aldosterone action andaldosterone deficient conditions such as hyporeninemic hypoaldosteronism, primary hypoaldosteronism including aldosterone synthasedeficiency (ASD) and acquired form, are reviewed. Pseudohypoaldosteronism, an aldosterone resistance syndrome due to insensitivityof target tissues to aldosterone, is also reviewed. For complete coverage of this and all related areas of Endocrinology, please visit ourFREE on-line web-textbook, www.endotext.org.

INTRODUCTIONAldosterone is crucial for sodium conservation in the kidney, salivary glands, sweat glands and colon. Aldosterone is synthesizedexclusively in the zona glomerulosa of the adrenal gland. Destruction or dysfunction of the adrenal gland in conditions such as primaryadrenal insufficiency, congenital adrenal hypoplasia, isolated mineralocorticoid deficiency, acquired secondary aldosterone deficiency(hyporeninemic hypoaldosteronism), acquired primary aldosterone deficiency and inherited enzymatic defects in aldosteronebiosynthesis cause clinical symptoms and laboratory characteristics owing to aldosterone deficiency. Pseudohypoaldosteronism is analdosterone resistance syndrome i.e. a condition due to insensitivity of target tissues to aldosterone. In this chapter, aldosterone deficientconditions other than primary adrenal insufficiency and congenital adrenal hypoplasia are reviewed.

ALDOSTERONE BIOSYNTHESISAll human steroid hormones are derived from cholesterol. Aldosterone is synthesized in the zona glomerulosa of the adrenal cortexthrough four enzymes, cholesterol desmolase (CYP11A1), 21-hydroxylase (CYP21A2), aldosterone synthase (CYP11B2) and 3β-hydroxysteroid dehydrogenase (3β-HSD) (Figure 1). CYP11A1, CYP21A2 and CYP11B2 are cytochromes 450 (CYP), which aremembrane-bound heme-containing enzymes that accept electrons from NADPH through accessory proteins and use molecular oxygento perform hydroxylations or other oxidative conversions (1). CYP11A1, which is a side-chain cleavage enzyme, cleaves the side chainfrom C21 of cholesterol, converting cholesterol to pregnenolone in adrenal mitochondria and this is the first step in steroidogenesis. TheCYP11A1 gene is located on the long arm of human chromosome 15q24-q25 (2). Pregnenolone is returned to the cytosolic compartmentand is converted to progesterone by 3β-HSD (3). Progesterone is then hydroxylated at C21 by CYP21A2, an enzyme located in thesmooth endoplasmic reticulum, to yield deoxycorticosterone (DOC). The CYP21A2 gene is located on the short arm of humanchromosome 6 (4). Only CYP21A2 is active in humans, the other, CYP21A1P is a pseudogene (5). CYP11B1, which is a mitochondrialenzyme, catalyzes β-hydroxylation at C11 and converts DOC to corticosterone. The terminal two steps in the conversion ofcorticosterone to aldosterone (18-hydroxylation and 18-methyloxidation) are catalyzed by CYP11B2 (aldosterone synthase) (6), whichwas previously named corticosterone 18-hydroxylase/18-methyloxidase (CMO I/CMO II) or 18-hydroxylase/isomerase. These two stepspreviously proposed to be catalyzed by separate enzymes, CMO 1 and II, are known to involve only one enzyme substrate interaction,aldosterone synthase encoded by CYP11B2 gene (6.1). The CYP11B1 and CYP11B2 genes are located on the long arm of chromosome8 and the amino acid sequence of CYP11B2 shares more than 90% homology with that of CYP11B1 (7,8). In humans, the expression ofCYP11B1 and CYP11B2 in the adrenal glands is spatially separated. While expression of CYP11B1 takes place in the zonareticularis/fasciculata, CYP11B2 expression and aldosterone synthesis are restricted to the zona glomerulusa (8.1).

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Figure 1

Aldosterone Biosynthesis. Aldosterone is derived from cholesterol. Biosynthetic pathway of aldosterone and structure of adrenalsteroids and their biosynthetic precursors are shown in the figure. The enzymes that catalyze each step are listed in the adjacent boxat the right side of the figure.

REGULATION OF ALDOSTERONE SECRETIONAldosterone secretion is regulated by multiple factors. The renin-angiotensin system and potassium ion are the major regulators,whereas ACTH and other POMC peptides, sodium ion, vasopressin, dopamine, ANP, β-adrenergic agents, serotonin and somatostatinare minor modulators.

The Renin-Angiotensin systemRenin is a 430 amino acid enzyme that cleaves renin substrate or angiotensinogen, which is a 453 amino acid a-globulin product of theliver, to produce the decapeptide, angiotensin I. Angiotensin I is rapidly cleaved by angiotensin-converting enzyme (ACE) in the lungand other tissues to form the octapeptide, angiotensin II. Moreover, angiotensinase cleaves the NH2-terminal Asp residue fromangiotensin II and produces the heptapeptide, angiotensin III, then to the hexapeptide angiotensin IV. The circulating levels ofangiotensin III are 15 to 25% of those of angiotensin II. Angiotensin II, III and IV stimulate aldosterone secretion and vasoconstriction,while angiotensin II is more potent for vasoconstriction. The angiotensins are inactivated within minutes by tissue and plasma peptidase.The levels of the circulating renin are the rate-limiting factor of this process.

Renin is synthesized by the juxtaglomerular cells in the renal cortex and its secretion is controlled by renal arterial blood pressure,sodium concentrations of tubular fluid sensed by the macula densa and renal sympathetic nervous activity (9). Factors that decreaserenal blood flow, such as hemorrhage, dehydration, salt restriction, upright posture and renal artery narrowing, increase renin levels. Incontrast, factors that increase blood pressure, such as high salt intake, peripheral vasoconstrictors and supine posture, decrease reninlevels. Hypokalemia increases and hyperkalemia decreases renin release (10).


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The effect of angiotensin II and III on the adrenal glomerulosa is initiated by binding to G-protein coupled receptors. The firstmechanism of the intracellular signal transduction is activation of phospholipase C, which hydrolyzes PIP2 to IP3, which then releasesintracellular calcium ions (11). Interestingly, angiotensin II does not stimulate adenylate cyclase activity (12). Angiotensin II stimulationleads to increased transfer of cholesterol to the inner mitochondrial membrane and increased conversion of cholesterol to pregnenoloneand corticosterone to aldosterone. (12, 13).

PotassiumPotassium directly increases aldosterone secretion by the adrenal cortex and aldosterone then lowers serum potassium by stimulating itsexcretion by the kidney. High dietary potassium intake increases plasma aldosterone and enhances the aldosterone response to asubsequent potassium or angiotensin II infusion (11). The primary action of potassium for stimulating aldosterone secretion is todepolarize the plasma membrane, which activates voltage-dependent calcium channels, that permit influx or exflux of extracellularcalcium (11), leading to the activation of calmodulin and calmodulin-dependent kinase, subsequently.The activated kinasephospholylates both activating transcription factor and members of CRE-binding protein family, which bind to 5’ flanking promotorregions of the CYP11B2 gene and trigger gene transcription in the zona glomerulosa, then increase aldosterone biosynthesis asangiotensin II does (13, 8.1, 13.1, 13.2).

Pituitary FactorsACTH and possibly other POMC-derived peptides, including α-MSH, α-MSH, β-LPH and β-END, influence aldosterone secretion,however, the role of ACTH in aldosterone secretion is minor (10). ACTH increases aldosterone secretion by binding to glomerulosacell-surface melanocortin-2 receptor, activating adenylate cyclase, and increasing intracellular cAMP (15). Like other agents, ACTHstimulates the same two early and late steps of aldosterone biosynthesis.

Vasopressin has a modest and transient stimulatory effect on aldosterone secretion from zona granulosa cells in vitro. This effect isprobably mediated via V2 receptors and phospholipase C generating IP3 and diacylglycerol (16).

SodiumSodium intake influences aldosterone secretion by an indirect effect through renin and to a minor extent by direct effects on zonaglomerulosa responsiveness to angiotensin II. High sodium intake increases vascular volume, which suppresses renin secretion andangiotensin II generation and decreases the sensitivity of aldosterone response to angiotensin II (17).

Inhibitory agentsDopamine inhibits aldosterone secretion in humans by a mechanism that is independent of the effects of prolactin, ACTH, electrolytesand the renin-angiotensin system (18). This inhibitory effect may involve binding to D2 receptors on glomerulosa cells (19). Atrialnatriuretic peptide (ANP) directly inhibits aldosterone secretion and blocks the stimulatory effects of angiotensin II, potassium andACTH, at least in part, by interfering with extracellular calcium influx (20).

MECHANISMS OF ALDOSTERONE ACTION: EFFECT OF ALDOSTERONEAldosterone is crucial for sodium conservation in the kidney, salivary glands, sweat glands and colon. Aldosterone promotes activesodium transport and excretion of potassium in its major target tissues. It exerts its effects via the mineralocorticoid receptor (MR) andthe resultant activation of specific amiloride-sensitive sodium channels (ENaC) and the Na-K ATP ase pump (21). Aldosterone and theMR may be involved in the regulation of genes coding for the subunits of the amiloride sensitive sodium channel and the Na-K ATP asepump, serum and glucocorticoid regulated kinase (SGK), channel-inducing factor, as well as of other proteins (22,23, 23.1). ActivatedSGK1 phosphorylates the neural precursor cell-expressed, developmentally down-regulated protein 4-2 (Nedd4-2) which allows bindingof 14-3-3 proteins (23.2). Then, the interaction of Nedd4-2 and ENaC causes an accumulation of ENaC at the plasma membrane andenhances epithelial sodium transport by increasing open probability of ENaC. In a later phase translation and allocation of ENaC,basolateral Na-K ATP ase and apical K channel (ROMK) are enhanced in its target tissues (24, 24.1, 24.2).

Rapid effects in response to aldosterone, , independent of the MR, were described as non-genomic or rapid signaling of aldosterone. TheG protein-coupled estrogen receptor (GPER) [previously known as G protein-coupled receptor 30 (GPR30)], a member of the seventransmembrane domain family of cell surface receptors, has been reported to be a membrane receptor for aldosterone (24.3). Theexpression of GPER is ubiquitous, including in vascular cells (both endothelial cells and smooth muscle cells) and is required for rapidMR-independent effects of aldosterone in vascular smooth muscle cells (24.3). Aldosterone has both vasodilator and vasoconstrictoreffects. The effect of aldosterone on endothelial function would vary depending on the balance between GPER and MR expression. Invascular endothelial cells, aldosterone activation of GPER mediates vasodilation, while activation of endothelial MR has been linked toenhanced vasoconstrictor and/or impaired vasodilator response (24.3, 24.4, 24.5).


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Mineralocorticoid ReceptorThe MR is found in the cytoplasm and nucleus and the sodium channels are expressed in the apical membrane of epithelial cells of thedistal convoluted tubule as well as in cells of other tissues involved with conservation of salt, such as colon, sweat glands, lung andtongue. MR is a member of the nuclear receptor superfamily. Together with the glucocorticoid, progesterone and androgen receptors,MR forms the steroid receptor subfamily (25). Steroid receptors display a modular structure comprised of five regions (A-E). TheN-terminal A/B region harbors an autonomous activation function. The central C region, corresponding to the DNA-binding domain, ishighly conserved and is composed of two zinc fingers involved in DNA binding and receptor dimerization. D region is a hydrophilicregion and it forms a hinge between DNA-binding domain and ligand-binding domain. E region corresponds to the C-terminal ligand-binding domain and mediates numerous functions, including ligand binding, interaction with heat-shock proteins, dimerization, nucleartargeting, and hormone-dependent activation (26) (Figure 2). The human MR (hMR) and human glucocorticoid receptor (hGR) havealmost identical DNA-binding domains (94% homology in the amino acid) and very similar ligand-binding domains (57%), butdivergent N-terminal A/B regions (<15%) (27). The hMR gene was mapped on chromosome 4q31.1-31.2 (28,29) and hMR cDNAencodes a 107 kilodalton polypeptide with 984 amino acids (27). The hMR gene consists of 10 exons, including two exons 1 that encodedifferent 5'-untranslated sequences (30). Expression of the two different hMR variants is under the control of two different promotersthat contain no obvious TATA element, but multiple GC boxes. Both hMRα and hMRβ mRNAs are expressed at approximately the samelevel in the mineralocorticoid target tissues (31).

Figure 2

The linearized structures of the mineralocorticoid receptor gene, mRNAs and protein. The MR gene consists of 10 exons. The MRhas two exons 1 (exon 1αand exon 1β), each with an alternative promoter; however, the finally translated MR protein is the same.Exons 1 are untranslated regions, exon 2 codes for the immunogenic domain (A/B), exons 3 and 4 for the DNA-binding domain (C),and exons 5-9 for the hinge region (D) and the ligand-binding domain (E). (From .Arai K, Shibasaki T, Chrousos GP.Pseudohypoaldosteronism: sporadic and familial mineralocorticoid resistance. In: Chrousos GP. Olefsky JM, Samols E, eds.Hormone Resistance and Hypersensitivity States. New York: Lippincott Williams & Wilkins; in press with permission)

Molecular and Cellular Mechanisms of the Aldosterone ActionMRs in its unliganded state is located in the cytoplasm, as part of hetero-oligomeric complexes containing heat shock proteins 90, 70and 50 (32). Upon binding with their ligand, the receptor-ligand complex dissociates from the heat shock proteins, homo- orheterodimerizes and translocates into the nucleus. Homodimers or heterodimers of the MR interact with hormone-responsive elements(HRE) and/or other transcription factors in the promoter regions of target genes, including the subunits of the ENaC or other proteinsrelated to this channel and sodium transport in general, and modulates the transcription rates of these genes (33) (Figure 3).


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Figure 3

Mechanism of aldosterone action on sodium reabsorption at the distal convoluted tubule of the nephron. Aldosterone binds to theMR, which is located in the cytoplasm in complex with heat shock proteins 90, 70 and 50. After binding, the receptor-ligandcomplex translocates into the nucleus, binds to hormone-responsive elements (HRE) of target genes where it modulates theirtranscription rate. Amiloride-sensitive sodium channel (ENaC) subunits or other related proteins may be targets of such regulation.(From Arai K, Chrousos GP. Glucocorticoid and mineralocorticoid resistance: clinical and molecular aspects. In: Vinson GP,Anderson DC eds. Adrenal Glands, Vascular System and Hypertension. Bristol, UK: Journal of Endocrinology Limited, pp211-226,1996, with modification and permission)

Pre-receptor RegulationSince cortisol circulates at plasma concentrations several orders of magnitude higher than those of aldosterone does, and since it has ahigh affinity for the MR, it would be expected to overwhelm this receptor in mineralocorticoid target tissues and causemineralocorticoid excess. A local enzyme, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), however, converts active cortisol toinactive cortisone, and protects the MRs from the effects of cortisol (34). 11β-HSD catalyzes the interconvension of hormonally activeC11-hydroxylated corticosteroids (cortisol in humans or corticosterone in rodents) and their inactive C11-keto metabolites (cortisone inhumans or 11-dehydrocorticosterone in rodents). Two isozymes of 11β-HSD have been identified, 11β-HSD type 1 (11β-HSD1) and11β-HSD2, which differ in their biological properties and tissue distributions. 11β-HSD2, a potent NAD-dependent 11β-hydrogenase,rapidly inactivates glucocorticoids. The human 11β-HSD2 gene encodes 405 amino acids and its molecular weight is approximately 40-kilodalton (35). 11β-HSD2 has a hydrophilic N-terminal domain that is thought to anchor the protein into membranes (36). 11β-HSD2 islocalized as a dimmer in the nucleus and cytoplasm of cells of the cortical collecting duct and colon (36,37). Prednisolone andprednisone are substrates for both 11β-HSD isozymes (38,39) and dexamethosone is metabolized slightly by 11β-HSD2 (40). Licoricederivatives, such as glycyrrhizic acid, and the hemisuccinate derivative carbenoxolone are inhibitors of 11β-HSD2. Inhibition of 11β-HSD2 with such agents derivatives confers mineralocorticoid potency to physiologic concentrations of endogenous glucocorticoids inthe kidney and colon (41). Thus, in normal physiology, 11β-HSD2 protects the MR by converting cortisol to the inactive cortisone andallows aldosterone-selective access to the inherently nonselective MR in mineralocorticoid target tissues.

Amiloride-sensitive sodium channel (Epithelial sodium channel; ENaC)The cDNA of the α-subunit of the ENaC (αENaC) was cloned from the rat colon in 1993 (42) and soon after the cDNAs of the β- andγ-subunits of this channel were cloned for the same species (43). The human α-, β- and γ-subunits of ENaC were also cloned recently(44,45). In vitro studies demonstrated that the α subunit of the ENaC itself had the majority of Na channel function, while, the β- and γ-subunits alone were not shown to play as major a role in sodium transport (42). However, the β- and γ-subunits enhanced the function ofthe α-subunit and all subunits are required for full ENaC activity (45.1). It appears then that this channel consists of the α-, β- andγ-subunits and an amiloride-binding protein (Figure 4). Aldosterone increases transcription of αENaC but not β- and γ-subunits,resulting enhanced channel assembly and transported from endoplasmic reticulum to Golgi (45.2). In Golgi, furin proteolytically cleavesspecific sites in the extracellular domains of α- and γ-ENaC, resulting channel activation (45.3). At the cell surface, Nedd4-2 binds toENaC, increasing endocytosis and degeneration (45.4-5).The proline-rich region of the C-terminal of the αENaC is important for


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binding to α-spectrin and for stabilization of the sodium channel in the membrane (46).

Recently, several studies demonstrated abnormalities of the β- and γ-subunits of the ENaC in patients with Liddle's syndrome,characterized by mineralocorticoid excess (hypertension and hypokalemic alkalosis), and suppressed aldosterone secretion (47-50). Thetruncation caused by these mutations influenced the PY motif at the N-terminal of the molecule. This motif is responsible for thebinding of the channel subunits with NEDD4, a carrier protein facilitating clearance of the channel (51). Moreover, a point mutation ofthe αENaC gene, located close to the N-terminal of the protein, was reported to cause a decrease of the probability of an open sodiumchannel, resulting in defective reabsorption (52,53).

The ENaC-regulatory complexes in aldosterone-mediated sodium transportAldosterone-induced transepitherial Na+ transport via ENaC involves the coordinate functioning of stimulatory signaling proteins suchas serum- and glucocorticoid-induce kinase-1 (SGK1) (23.1, 53.1), glucocorticoid-induced leucine zipper protein-1 (GILZ1) (53.2) andconnector enhancer of kinase suppressor of Ras 3 (CNK3) (53.3), with inhibitory proteins, such as neural precursor cell expressed,developmentally downregulated protein (Nedd4-2) (23.2) and extracellular signal-regulated kinase (ERK) 1/2 (53.9).

SGK1 is an aldosterone-regulated protein kinase that stimulates renal ENaC. SGK1 phosphorylates the E3 ubiquitin ligase, Nedd4-2,and inhibits it. Nedd4-2 interacts with the C-terminal tail of ENaC subunits, decrease surface expression of the channel via channelubiquitinylation (23.1, 23.2, 53.1). Then, SGK1 alters ENaC expression, trafficking and activity, and stimulates Na+ transport in thekidney cortical collecting duct (CCD) (53.4). However, SGK1 is a short-lived protein. Following synthesis, SGK1 is rapidly targeted tothe endoplasmic reticulum (ER), where ER-associated ubiquitin ligases CHIP and HRD1 aid in its ubiquitinylation and subsequentproteasome-mediated degradation (53.5) Another aldosterone-induced ENaC-regulator, GILZ, which protects SGK1 from rapid ER-associated degradation by controlling protein-protein interaction (53.6). In kidney CCD, GILZ1 is robustly induced by aldosterone(53.7). GILZ1 stimulates ENaC cell surface expression and activity at least in part by inhibiting ERK1/2, which abrogates ENaCfunction (53.6, 53.8, 53.9).

The recently identified MR target gene CNKSR3 (connector enhancer of kinase suppressor of Ras 3), commonly referred as CNK3, ishighly expressed in the connecting tubule (CNT) and the CCD (53.10). CNK3, like SGK1 and GILZ1, is rapidly induced byphysiological concentrations of aldosterone (53.3). It is speculates that CNK3 acts to assembly various ENaC-regulatory components inclose vicinity of the channel and thereby exerts its stimulatory effects on channel function (53.11).

Epigenetic control of ENaC transcription by aldosterone-sensitive Dot1A-Af9 complexChromatin regulates gene transcription by the post-translational modification of histone N-terminal tails such as acetylation andmethylation. The histone H3 Lys 79 methyltransferase disruptor of telomeric silencing alternative splice variant a (Dot1a) methylateshistone H3 Lys79, which resides in the globular domain (53.12). ALL-1 fused gene from chromatin 9 (Af9), putative transcriptionfactor, physically and functionally interact with Dot1a to form a nuclear repressor complex that directly or indirectly binds specific siteof the ENaC promoter, leading to hypermethylation of histone H3 Lys 79 and repression of ENaCtranscription (53.13). Aldosteronedown-regulates the Dot1a -Af9 complex, leading to targeted histone H3 Lys-79 hypomethlation and transcriptional activation of ENaC.While ALL-1 fused gene from chromatin 17 (Af17) competes Af9 to bind Dot1a and relieves Dot1a-Af9-mediated repression of ENaC.In addition, aldosterone-induced Sgk1 phosphorylates Af9, thus down-regulates Dot1a-Af9 complex, leading to relieve basal repressionon ENaC transcription (53.15).


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Figure 4

Model of a putative amiloride-sensitive sodium channel (ENaC). The amiloride-sensitive sodium channel appears to consist of theα-, β- and γ- subunits and an amiloride-binding protein. This channel is located at the apical site of the renal epithelium and plays arole in passive sodium transport, which is mainly regulated by mineralocorticoids. (From Arai K, Shibasaki T, Chrousos GP.Pseudohypoaldosteronism: sporadic and familial mineralocorticoid resistance. In: Chrousos GP. Olefsky JM, Samols E, eds.Hormone Resistance and Hypersensitivity States. New York: Lippincott Williams & Wilkins; in press with permission)

CLASSIFICATION OF HYPOALDOSTERONISMVarious syndromes are characterized by or associated with hypoaldosteronism. Hypoaldosteronism is classified in three large categories,defective stimulation of aldosterone secretion, primary defects in adrenal synthesis or secretion of aldosterone and aldosteroneresistance, according to their pathophysiology and summarized in Table 1.


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Defective Stimulation of Aldosterone SecretionThe first category of conditions, which is characterized by defective stimulation of aldosterone secretion, includes the syndromes ofcongenital and acquired hyporeninemic hypoaldosteronism. One of these conditions is due to a defect of renin secretion such ashyporeninemia resulting from β-blockers, prostaglandin synthetase inhibitors, and calcium channel blockers. Another condition is due todecrease in the conversion of angiotensin I to angiotensin II mediated by converting enzyme inhibitor medications and is associated withhyperreninemia.

Primary Defects in Adrenal Biosynthesis or Secretion of AldosteroneThe second category of conditions, which are characterized by primary defects in adrenal synthesis or secretion of aldosterone, includesall causes of primary adrenal insufficiency and primary hypoaldosteronism caused by aldosterone synthase (CYP11B2) deficiency or asan acquired state. Primary adrenal insufficiency causes include congenital adrenal hypoplasia, congenital adrenal hyperplasia,adrenoleukodystrophy/adrenomyeloneuropathy, acquired adrenal insufficiency due to autoimmune, infectious and infiltrative disease,bilateral adrenalectomy and use of adrenolytic agents and enzyme inhibitors that block cortisol and aldosterone biosynthesis. Theseconditions are usually combined with defective cortisol synthesis. Aldosterone synthase (CYP11B2) deficiency (ASD) leads to reducedaldosterone production associated with low or high levels of 18-hydroxycorticosterone, referred to as CMO I or CMO II deficiency,respectively. Several conditions may be associated with aldosterone biosynthetic activity. Heparin suppresses aldosterone synthesis.Critically ill patients with persistent hypovolemia and hypotension also have inappropriately low plasma aldosterone concentrations inrelation to the activity of the renin-angiotensin system. Isolated primary hypoaldosteronism in occasionally associated with metastaticcancer of the adrenal gland.

Defective Aldosterone ActionsThe third category which is characterized by defective aldosterone action includes syndromes of aldosterone resistance such aspseudohypoaldosteronism type 1 and sodium-wasting states resulting from excessive amounts of circulating mineralocorticoidantagonists, such as spinololactone and its analogues, and synthetic progestin or natural agonists, such as progesterone or 17-hydroxyprogesterone. These mineralocorticoid antagonists may antagonize aldosterone at the levels of mineralocorticoid receptor (54)and frequently, these states are compensated for by elevated concentrations of plasma aldosterone.

HYPORENINEMIC HYPOALDOSTERONISM: PresentationThe most common form of isolated hypoaldosteronism is caused by impaired renin release from the kidney. Hudson et al. first describedthis syndrome in 1957 (55), however, hyporeninemia was first recognized in 1972 (56,57). The typical patient is 50 to 70 years old andusually presents with chronic and asymptomatic hyperkalemia and mild to moderate renal insufficiency with a 40-70% decrease in theglomerular filtration rate when compared to that of age matched healthy subjects. Hyperchloremic metabolic acidosis is seen inapproximately half of the patients. This acidosis is classified as a renal tubular acidosis type IV (58). The acidosis is a consequence ofdecreased renal ammonia neogenesis, reduced hydrogen ion-secretory capacity in the distal nephron and mild reduction in the proximaltubular threshold for bicarbonate reabsorption. Occasionally, muscle weakness or cardiac arrhythmias are present in some patients. Morethan a half of the patients have diabetes mellitus (59). Other frequently associated states include autonomic neuropathy, hypotension andvarious nephropathies such as glomerulonephritis, gouty nephropathy and pyelonephritis (60). Also, this syndrome is associated withnephropathies of multiple myeloma and systemic lupus erythematosus, mixed cryoglobulinemia, nephrolithiasis, analgesic nephropathy,renal amyloidosis, IgA nephropathy, cirrhosis, sickle cell anemia, acquired immune deficiency syndrome (AIDS), polyneuropathy,organomegaly, endocrinopathy, M protein and skin changes (POEMS) syndrome, lead poisoning, excess sodium bicarbonate andSjögren’s symdrome (61-68, 68.1, 68.2). Moreover, this syndrome occurs transiently in association with use of non-steroidal anti-inflammatory drugs, cyclosporin A, mitomycin C, cosyntropin and other agents in susceptible individuals (69-72).

PathophysiologyUrinary aldosterone excretion is low under basal conditions and fails to increase after sodium restriction. Plasma renin activity is alsolow and does not increase appropriately during sodium restriction, periods of prolonged upright posture, or diuretic administration (56).Interstitial renal disease and damage to the juxtaglomerular apparatus seems the most likely cause for the primary defect in reningeneration or release and secondary deficiency of aldosterone. However, in some patients with this syndrome there is an absent orblunted aldosterone response to angiotensin II (73,74), suggesting a coexisting primary defect in aldosterone secretion or it reflectsatrophy of the zona glomerulosa caused by chronic renin deficiency.

There are various mechanisms to be explained the hyporeninemia. First possible mechanism is the hypervolemia. The expandedextracellular fluid volume due to hypertension may suppress renin. In fact, long-term sodium restriction and diuretic administrationincrease plasma renin activity in these patients, however, the increments of plasma renin activity are less than those of normal subjects(75). A second possible mechanism is insufficiency of the autonomic nervous system, particularly in patients with diabetic neuropathy.


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Impaired adrenergic response to postural change may contribute to insufficient renin release. Besides, these patients exhibit decreasedsensitivity to β-adrenergic agonists, suggesting defects in both production and action of catecholamines (76). A third proposedmechanism is secretion of abnormal forms of renin, such as a defect in the conversion of prorenin to renin. Insufficiency of autonomicnervous system may be associated with impaired conversion of prorenin to renin. Indeed, diabetic patients with autonomic neuropathyhave elevated plasma levels of prorenin (77). A fourth possibility is prostaglandin deficiency. Production of prostaglandin I2(prostacyclin), which mediates renin release (78), is apparently diminished in patients with hyporeninemic hypoaldosteronism asassessed by measurement of the stable urinary metabolite 6-keto-prostaglandin F1α (79). Furthermore, the prostaglandin I2 in thesepatients was unresponsive to the potent stimulators norepinephrine and calcium. Prostaglandin I2 deficiency may cause hyporeninemichypoaldosteronism by causing defects in the conversion of prorenin to renin (80) and renin release.

DiagnosisThe diagnosis of hyporeninemic hypoaldosteronism must be considered in any patient with unexplained hyperkalemia. Excesspotassium intake from food or drugs does not cause sustained hyperkalemia, if renal function is normal. Renal function should beevaluated and drugs that impair renal potassium excretion should be excluded as a cause. The clinical diagnosis is confirmed by lowplasma renin activity and low plasma concentrations or urinary aldosterone excretion under conditions that activate the renin-angiotensin-aldosterone axis suc h as maintenance of upright posture and/or furosemide administration. A low random plasma reninconcentration associated with a normal ratio of aldosterone to plasma renin activity is also useful for the diagnosis (81,82).

TherapyThe therapeutic approach should be chosen after taking into consideration the age of the patients and other concurrent disorders. Onlymonitoring potassium concentrations is enough for patients with moderate hyperkalemia and without electro-cardiographic changes.Drugs that promote hyperkalemia, such as β-adrenergic antagonists, cyclooxygenase inhibitors, angiotensin-converting enzymeinhibitors, heparin and potassium-sparing diuretics, should be avoided. Dietary potassium intake should be reduced, if possible.Diuretics are the initial treatment for patients who have disorders associated with sodium retention, such as hypertension and congestiveheart failure. Mineralocorticoid replacement with fludrocortisone is reserved for patients with severe hyperkalemia without hypertensionand congestive heart failure.

PRIMARY HYPOALDOSTERONISM: Aldosterone Synthase Deficiency (ASD)Congenital hypoaldosteronism is a rare inherited disorder transmitted as either an autosomal recessive or autosomal dominant trait withmixed penetrance. This disorder was previously termed "corticosterone methyloxidase (CMO)” deficiency and subdivided into twotypes according to the relative levels of aldosterone and its precursors in an affected person. Patients with "corticosterone methyloxidaseI (CMO I)" deficiency have elevated serum levels of corticosterone and low levels of 18-hydroxycorticosterone and aldosterone. Incontrast, patients with "corticosterone methyloxidase II (CMO II)" deficiency have high levels of 18-hydroxycorticosterone, theimmediate precursor of aldosterone (83). With greater understanding of structure-activity relationships in the CYP11B2 enzyme, thisdisorder may be better considered a spectrum of hormonal deficiencies, depending on the nature of the CYP11B2 gene defect (88.6).Because two steps of aldosterone biosynthesis from corticosterone previously proposed to be catalyzed by separate enzymes, CMO Iand II, previously, are known to involve only one enzyme substarate interaction (6.1). Isolated aldosterone deficiency results from lossof activity of aldosterone synthase encoded by CYP11B2 gene (84-88,88.1,88.2,88.3-5). Therefore, the term aldosterone synthasedeficiency type 1 (ASD1) and type 2 (ASD2) reflects more appropriately the molecular basis of this disease. In both ASD1 and 2,glomerulosa zone corticosterone is increased and aldosterone decreased, but 18-hydroxycorticosterone is increased in ASD2 (88.6).ASD1 is associated with loss of both 18-hydroxilation and 18-oxidation enzyme activities. In ASD2, the ability to convertcorticosterone (B) to 18-hydorxytetrahydro11-dehydrocorticosterone (18-OH-B) is preserved with failure of further oxidation of 18-hhdroxicorticosrerone to aldosterone (88.7). The deficiency of aldosterone is much more severe in ASD1. In contrast, aldosterone mayreach normal levels under intense stimulation of rennin-angiotensin system in ASD2 (88.6). The clinical presentations of thesedeficiencies are otherwise similar. The clinical presentation is typical of aldosterone deficiency, including electrolyte abnormalities suchas a variable degree of hyponatremia, hyperkalemia and metabolic acidosis, with poor growth in childhood, but they usually nosymptoms in adults (83,89). In infants, it is characterized by recurrent dehydration, salt wasting and failure to thrive. These symptomsare present generally within the first 3 months of life, and most often after the first 5 days of life. A modest uremia with a normalcreatinine level reflects dehydration in the presence of intrinsically normal renal function. Plasma renin activity is invariably elevated.

Diagnosis and TherapyThe diagnosis can be established by measuring the appropriate corticosteroids or their major metabolic products, such as 11-deoxycorticosterone (DOC), corticosterone, 18-hydroxycorticosterone, 18-hydroxy-DOC and aldosterone levels in plasma. The ratio ofplasma 18-hydroxycorticosterone to plasma aldosterone differentiates the two disorders; it is less than 10 in ASD1 (CMO I deficiency)and more than 100 in ASD2 (CMO II deficiency) (90). Patients with ASD2 (CMO II deficiency) tend to have increased plasma cortisol


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levels that may result from increased adrenal sensitivity to ACTH induced by the increased plasma angiotensin II levels in response tosodium depletion (91).

Both forms of the syndrome are treated by replacement of mineralocorticoid with the usual dosage of fludrocortisone (0.1-0.3 mg/ day).Almost infants and children require oral sodium supplementation (2 g/day as NaCl alone or in combination with NaHCO ), althoughsome infants with severe symptom need intravenous fluids. Oral sodium supplementation may be discontinued once plasma renninactivity has decreased to normal, but mineralocorticoid replacement is usually maintained through childhood (88.7).

Molecular mechanisms of CYP11B2 deficiencySome patients with ASD1 (CMO I deficiency) have a homozygous 5 nucleotide deletion in exon 1 which leads to a frameshift andpremature stop codon, resulting in the complete lack of enzyme production (84,85). A male Caucasian patient with ASD1 (CMO Ideficiency) had a homozygous point mutation causing a R384P substitution, resulting in complete loss of 11 β- and 18-hydroxylaseactivity (86) (Figure 5). This suggests that the arginine-384 in aldosterone synthase is highly conserved and apparently quite importantfor enzyme activity.

A male infant of Turkish parents who presented ASD1 had homozygous missense mutation (L451F) in exon 8 of CYP11B2 gene. TheL451F mutant protein in vitro showed complete aldosterone deficiency with 11-deoxycirticosterone or corticosterone as substrates. TheL451F mutation located immediately adjacent to the highly conserved heme-binding C450 of the cytochrome P450 (88.4). Computermodeling of the molecule suggested that this substitute my lead a steric effect resulting in preventing the activity of CYP11B2 (88.4).

Three siblings of Pakistan origin who presented ASD1 had homozygous mutation (S308P) in exon 5 of CYP11B2 gene. The S308Pmutant protein in vitro showed complete loss of enzyme activity. This mutated residue is likely to locate within the a-helix I, close to theheme-binding, active site of the enzyme. This structural change may be the cause of this disorder in this family (88.5).

A large number of kindreds with ASD2 (CMO II deficiency) have been identified among Jews originally from Isfahan, Iran. Suchpatients are all homozygous for two mutations, R181W in exon 3 and V386A in exon 7 (85,87,88, 88.3,88.7) (Figure 5). Thesemutations together reduce aldosterone synthase activity to 0.2 % of normal without affecting 11 β-hydroxylase activity (85,87,88).However, one non-Iranian patient with ASD2 (CMO II deficiency) carries mutations in the paternal allele, including V386A and T318Amutations, and maternal allele, including R181W and a deletion/frameshift mutation, resulting in complete loss of enzyme activity (88).This suggests that the high levels of 18-hydroxycorticosterone seen in ASD2 (CMO II deficiency) can be synthesized by CYP11B1,which has some 18-hydroxylase activity, and not by CYP11B2. A patients with apparent ASD 1 was homozygous for the mutationsE198A and V386A, yet when assayed in vitro the double mutant enzyme behaved similarly to the mutant enzyme found in the IranianJewish ASD 2 patients (88.9).Thus, a difference in expression of CYP11B1 rather than allelic variation of CYP11B2 may be involved inthe mechanism underlying the different levels of 18-hydroxycorticosterone between ASD1 and 2 (CMO I and CMO II deficiency). Thedistinction between ASD 1 and ASD 2 is not precise, and these disorders should be regarded as different degrees of severity on acontinuous clinical spectrum.

A male Japanese patient with ASD1 (CMO I ) was a compound heterozygous for W56X in exon 1 and R384W in exon 7. W56X wasinherited from his mother and R384X was from his father. Since both alleles contain nonsense mutations, a lack of CYP11B2 activitywas speculated to cause his condition (88.10).

Two male Japanese patients with ASD2 (CMO II) have homozygous missense mutation (G435S) in the exon 8 of CYP11B2 gene. Theexpression studies indicated that the steroid 18-hydroxylase/oxidase activities of mutant enzyme were substantially reduced.

A female infant of Albanian origin with ASD2 (CMO II) revealed homozygosity for a pathogenic T185I mutation in Exon 3 of theCYP11B2 gene and two other homozygous polymorphisms F168F and K1738 in Exon3 (88.11). Both healthy parents wereheterozygous for all three substitutions.

Another female Italian Caucasian patient was a compound heterozygous mutation located in exon 4 causing a premature stop codon(E255X) and a further mutation in exon 5 that also cause a premature stop codon (Q272X). The patient’s CYP11B2 encodes twotruncated forms of aldosterone synthase predicted to be inactive because they lack critical active site residues as well as the hormone-binding site. However, this case displays biochemical features intermediate between those of ASD1 and 2 (CMO I and II).

Some cases of ASD without causative mutations in CYP11B2 have also been reported (88.3,88.7).

3


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Figure 5

Relative positions of CYP11B1 and CYP11B2 on chromosome 8 and mutations of CYP11B2. A, The relative positions of CYP11B1and CYP11B2 on chromosome 8q22. Arrows indicate direction of transcription. B, Mutations of CYP11B2 in reported patients withCYP11B2 deficiency are summarized in the figure. A deletion of 5 base pair (Δ35) in exon 1, R384P in exon 7 and L451F in exon 8have been reported in patients with aldosterone synthase deficiency type 1 (ASD1), previously termed as “corticosteronemethyloxidase type 1 (CMO I) deficiency”. R181W in exon 3, V386A and T318A in exon 7 and G453S in exon 8 have beenreported in patients with aldosterone synthase deficiency type 2 (ASD2), previously termed as “corticosterone methyloxidase type 2(CMO II) deficiency”. Compound heterozygous mutation of E255X and Q272X have been found in the patient with unusual ASD(CMO).

Acquired form of primary hypoaldosteronismSeveral conditions may be associated with aldosterone biosynthetic defects. The administration of heparin causes natriuresis andhyperkalemia (92). Heparin preparations suppress aldosterone synthesis, leading to a compensatory rise in plasma renin activity.However, it has been demonstrated that this suppression of enzyme activity is attributable to chlorbutol (1,1,1-trichloro-2-methyl-2-propanol), the preservative used in commercial heparin, rather than to pure heparin (93).

Persistently hypotensive, critically ill patients with sepsis, pneumonia, peritonitis, cholangiitis and liver failure, also haveinappropriately low plasma aldosterone concentrations in relation to elevated plasma renin activity (94). The defect is at the level of theadrenal but has not been associated with any particular disease or therapy. Plasma cortisol levels are high, reflecting the stressed state.The response to angiotensin infusion is impaired, and the ratio of plasma 18-hydroxycorticosterone to aldosterone is increased,suggesting selective insufficiency of CMO II. It is possible that the hypoxia causes a relative zona glomerulosa insufficiency (95).

ALDOSTERONE RESISTANCE: Pseudohypoaldosteronism (PHA) type 1Mineralocorticoid resistance (pseudohypoaldosteronism type 1, PHA1) results from inability of aldosterone to exert its effect on itstarget tissues and was first reported by Cheek and Perry as a sporadic occurrence in 1958 (96). This disease, usually presents in infancywith severe salt-wasting and failure to thrive, accompanied by profound urinary sodium loss, severe hyponatremia, hyperkalemia,acidosis, hyperreninemia and paradoxically markedly elevated plasma and urinary aldosterone concentrations. Usually, renal andadrenal functions are normal. This disease has been reported in over 70 patients (97). Approximately one fifth of these cases werefamilial, and both an autosomal dominant and a recessive form of genetic transmission were observed. All patients had renal tubularunresponsiveness to aldosterone, while some had involvement of other mineralocorticoid target-tissues, including the sweat and salivaryglands, and the colonic epithelium, as well. Autosomal recessive PHA1 presents in the neonatal period with hyponatremia caused bymulti-organ salt loss, including kidney, colon, and sweat and salivary glands. Autosomal recessive PHA1 persists into adulthood andshows no improvement over time (97.1). In contrast, autosomal dominant PHA1 is characterized by an isolated renal resistance toaldosterone, leading to renal salt loss. Particularly autosomal dominant form of PHA1 typically shows a gradual clinical improvement


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during childhood, allowing the cessation of sodium supplementation.

PathophysiologyThe mechanism(s) by which aldosterone controls sodium transport in its target tissues involves the mineralocorticoid receptor (MR) andproteins that are associated with the amiloride-sensitive sodium channel (ENaC). The latter proteins are expressed in the apicalmembrane of epithelial cells of the distal convoluted tubule and in the membranes of cells of other tissues involved in the conservationof salt, such as colon, sweat gland, lung and tongue. Thus, the MR and the ENaC were considered as potential candidate molecules forthe pathogenesis of PHA1. In fact, mutations of α- and β-subunits of the ENaC were reported in PHA patients from autosomal recessivekindreds (52,98). Mutations of the MR were also reported in the patients with autosomal dominant PHA1 (99, 100). However, nomolecular defects were found in either MR or ENaC in some patients with PHA1, especially in those with the sporadic form PHA1,which suggests molecular heterogeneity in PHA1 (101-107).

DiagnosisElectrolyte profiles suggest mineralocorticoid deficiency or end-organ resistance, along with hyperkalemia, hyponatremia and metabolicacidosis associated with profound urinary salt loss. Renal and adrenal function is normal. The diagnosis is confirmed as markedlyelevated plasma aldosterone concentrations and plasma renin activity.

The differential diagnosis of PHA1 includes salt-wasting states due to hypoaldosteronism, including several forms of congenital adrenalhyperplasia, isolated hypoaldosteronism due to corticosterone methyloxidase (CMO) I and II deficiencies and congenital adrenalhypoplasia. Normal cortisol and excessive aldosterone responses to adrenocorticotropin (ACTH) are expected in patients withcongenital PHA.

TherapyThe standard treatment of PHA has been replacement with high doses of salt, with a variable response among patients (97). Recently,carbenoxolone, an 11β-hydroxysteroid dehydrogenase inhibitor, was employed as therapy in PHA1 and an ameliorating effect wasobserved which was attributed to mediation by the MR (101). We studied a 17-yr-old male patient with congenital multifocal target-organ resistance to aldosterone. We examined his clinical response to carbenoxolone, expected to increase the intracellular level ofcortisol in the kidney by preventing local conversion of cortisol to cortisone, and to high doses of fludrocortisone, a syntheticmineralocorticoid. Subsequently, and for a brief period of time, we administered dexamethasone, which has no intrinsic salt-retainingactivity, in addition to carbenoxolone, to suppress endogenous cortisol, along with its intrinsic mineralocorticoid activity.

Figure 6

Effect of carbenoxolone, carbenoxolone plus dexamethasone, and fludrocortisone (top panel) on the serum sodium (middle panel)


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and potassium (bottom panel) concentrations of a patient with PHA. Carbenoxolone normalized plasma electrolytes, addition ofdexamethasone reversed this effect, while fludrocortisone at high doses also normalized plasma electrolytes. (From reference 101,with permission)

Carbenoxolone normalized the patient's serum electrolyte concentrations and decreased his urinary excretion of sodium within a week(Figure 6, above). Subsequent long-term therapy of this patient with carbenoxolone (450 mg/day p.o.) maintained his electrolyteconcentrations within the normal range. His urinary 24 h free cortisol was increased during carbenoxolone therapy. Addition ofdexamethasone suppressed his urinary free cortisol excretion and reversed the beneficial effect of carbenoxolone on serum and urinaryelectrolytes (Figure 6). These data suggest that an increase in urinary free cortisol observed during carbenoxolone therapy was due to alocalized effect of this drug on the kidney rather than on tissues involved in the negative feedback effect of glucocorticoids. The effectof carbenoxolone does not seem to be mediated by GR, but seems to be exerted purely via the MR (Figure 7). There were no adverseeffects of long-term carbenoxolone therapy in this patient. He also reported increased stamina, a better ability to concentrate and lessanxiety. On treatment, the patient grew 6 cm/y and progressed from -4SD to -3SD scores for mean height for age. He also progressed inhis pubertal development from Tanner stage III to IV for pubic hair, while his bone age advanced from 12 to 14 y.

Figure 7

Mechanism of the effect of carbenoxolone. Carbenololone inhibits of conversion of cortisol to cortisone in the kidney, resulting inthe enhancement of the effect of cortisol as a ligand for MR. Dexamethasone suppressed cortisol production and reversing thebeneficial effect of carbenoxolone in our patient with PHA1.

Both carbenoxolone and fludrocortisone normalized the serum electrolytes of our patient, suggesting the presence of a functional, albeitpossibly defective, renal MR. Interestingly, the same patient was unresponsive to intravenous infusion of aldosterone andfludrocortisone (up to 3 mg/day) when studied in infancy (108), suggesting that the clinical improvement that has been noted in themajority of PHA patients with age may be related to changes in their responsiveness to mineralocorticoid.

On the other hand, Hanukoglu et al reported that carbenoxolone did not show any significant salt-retaining effect in two patients withmultiple PHA, while carbenoxolone significantly suppressed the renin-aldosterone system in a renal PHA patient (108.1). Thisdifference of responsiveness to carbenoxolone may be due to an age-dependent change on mineralocorticoid responsiveness. Also thedifferent mineralocorticoid responsiveness of renal and multisystem PHA patients indicates a difference in their MR function. Thepartial response to carbenoxolone in renal PHA suggests that there is at least a partly functional MR. This is also supported by theobservation that spironolactone, a mineralocorticoid antagonist, aggravated sodium loss in several patients with renal PHA (108.2).

Molecular Mechanism(s) of Pseudohypoaldosteronism type 1


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In 1996, Chang et al. reported homozygous mutations introducing a stop codon or frame shift in the αENaC gene of affected membersof families with autosomal recessive PHA (52). More recently, in Swedish families with autosomal recessive PHA, homozygous orcompound heterozygous mutations introducing a stop codon or a frame shift in the αENaC gene were associated with pulmonary diseaseas well (109). The truncation caused by these mutations influenced the PY motif at the N-terminal region of the molecule. This motif isresponsible for the binding of the channel subunits with Nedd4, a carrier protein facilitating clearance of the channel (51,45.4).Moreover, a point mutation of the αENaC gene, located close to the N-terminal of the protein, was reported to cause a decrease of theprobability of an open sodium channel, resulting in defective reabsorption (52,110). In other four families with autosomal recessivePHA, insertion of a T in exon 8 and nonsense mutation (R508X) in exon 11 of the αENaC gene, these resulting in a truncated αENaCsubunit, were found (110.1). A splice site mutation in intron 12 of the βENaC gene, which preventing correct splicing of the mRNA wasfound in a Scottish patient (110.1). Also, other autosomal recessive families with PHA had a homozygous splice-site mutation in theγENaC, while a Japanese sporadic patient with the systemic form of PHA was a compound heterozygote for mutations in the αENaC,which resulted in the generation of a truncated channel subunit (98,111). Compound heterozygous mutations (Q217X in exon 4 andY306X in exon 6) of βENaC have been reported in the patient with multi-organ PHA1 of Ashkenazi family in Israel (110.2). Thesemutations produce shortened βENaC subunits with 253 and 317 residues respectively instead of the 640 residues present in βENaCsubunit. Expression of cRNA carrying these mutations in Xenopas oocytes showed that the either mutation drastically reduced to only3% of normal ENaC activity (110.2). An African American female with PHA, who had persistent and symptom hyperkalemia, hadcompound heterozygous mutation in the βENaC gene: c.1288delC in exon 9, a one-base deletion that generated a frameshift mutation,and c.1466+1 G>A, an intronic base substitution in intron11 that lead to a splice site mutation (110.3).

To date more than 50 different mutations in the human MR gene causing autosomal dominant PHA1 have been described. Nonsensemutations, frameshift mutations, splice site mutations and deletions of whole or part of the gene lead to gross change of the MR protein.Nonsense mutations are found in all exons and lead to truncated MR protein. For the first time, Geller et al. reported families withautosomal dominant PHA, who had molecular defects of the MR resulting in non-expression of one of the 2 alleles (99) (Figure 8). Inaddition, Viemann et al. reported a sporadic patient with PHA who had a heterozygous mutation in exon 9 of the MR that introduced apremature stop codon (107) (Figure 8). From these studies, one can conclude that expression of only one allele of the MR is insufficientto prevent salt loss. The Viermann et al. study did not identify any abnormalities of the MR in PHA patients from two families with theautosomal dominant form of the disease (107), while Tajima et al. reported a heterozygous missense mutation in exon 8 of the MR geneidentified in PHA patients from a Japanese autosomal dominant family (100) (Figure 8). A heterozygous nonsense mutations in exon 2(S163X, C436X) and in exon 9 (R947X) of the MR, leading to a premature stop codon of the MR gene were found in other patients withautosomal dominant PHA (107.1, 107.2, 107.3). Kanda et al. reported a heterozygous splice acceptor site mutation, which results inexon 7 skipping and subsequently in premature termination in exon 8 of MR with Japanese female patients with PHA1 (107.5). In theirstudy, RT-PCR products of mRNA with that patient showed both wiled-type and mutated mRNA, suggesting that haploinsufficiency dueto nonsense mediated mRNA decay with premature termination is not sufficient to give rise to the PHA phenotype (107.5). Sartorato etal. reported that Q776R mutation in exon 5 or L979P mutation in exon 9, which located in the ligand-binding domain of the MR,presented reduced or absent aldosterone binding, respectively (107.4). Three-dimensional structure of MR suggests that the residueQ776 is located in helix 3 and is locking aldosterone in the ligand-binding pocket (107.4). Ripe et al. studied patients with PHA1presenting isolated renal salt loss from six families in Italy and Germany and found one nonsense mutation (E378X), one frameshiftmutation (A958R) and two missense mutations (S818L and E972G) (107.6). S818L dose not bind aldosterone or activate transcriptionor translocate into the nucleus. Three-dimensional molecular structure showed that S818 was located in helix H5 and S818 wasspeculated to be necessary to stabilize helix H5 and the b-sheet 1 via hydrogen bond to Y828. E972G mutation showed a significantlylower ligand-binding affinity and only 9% of wild-type transcriptional activity. Three-dimensional molecular structure showed that E972is involved in a hydrogen-bond network with R947 anchoring helix H12 to H10. Thus, substitute of E972G suggested to be open up thehydrophobic core and displace helix H10, causing the decreased ligand-binding ability (107.6).

Hotta et al. reported four sporadic Japanese patients and two siblings with a renal form of PHA (107.7). Two siblings and one sporadicpatients had R651X of NR3C2 (MR) gene. One sporadic patient had R947X, another two patients had 603A deletion and 304-305CGdeletion, respectively, both resulting in frameshift mutations (107.7).

Morikawa et al. reported two female Japanese infants with the renal form of PHA1 and identified two heterozygous mutations. One hada c.4932_493insTT in Exon 2, resulting in a premature stop codon (p.Met166 LeufsX8) and another had a nonsense mutation of R861Xin exon 7 (107.8). These mutations resulted in haploinsufficiency of the MR and were the cause of aldosterone resistance in the kidney.

These studies suggest major molecular heterogeneity in PHA.

in non-expression of one of the 2 alleles of the MR.


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Figure 8

Mutations of the MR in patients with PHA1. Mutations of the MR that have been reported in patients with PHA1 are summarized inthe figure. G633R, Q776R, L924P and L979P are missense mutations and others are nonsense mutations, resulting in non-expression of one of the 2 alleles of the MR.

We studied 5 unrelated cases of sporadic PHA (101,105,106). We found a nonconservative homozygous mutation (A241V) in the MR of4 of the patients and a conservative heterozygous mutation (I180V) in one of these patients and his asymptomatic father, while noabnormalities were found in the DNA- or ligand-binding domains of the MR. The Val241 and Val180 substitutions were found also inthe normal population. The heterozygosity and homozygosity frequencies of the Val241 and Val180 mutations were 48%, 38%, 22% and1.5%, respectively. We also found a nonconservative amino acid substitution (T663A) in the αENaC, which was located close to theC-terminal (106). Of the 5 patients, 2 were homozygous and 3 heterozygous for this variation, respectively. This amino acid substitutionwas also present at high frequency in apparently normal controls. The homozygosity and heterozygosity frequencies of the αENaCAla663 were 31% and 64%, respectively. Three of the 4 (75%) patients with multiple tissue resistance to aldosterone had both αENaC(heterozygous or homozygous) and MR (homozygous) mutations as described above, while only 7% of our controls with apparentlynormal salt conservation had the same concurrent abnormalities (Table 2, p < 0.025).

Table 2 MR and aENaC polymorphisms in PHA and normal subjects

MR αENaC Target organ

I180V A241V T663A

homo hetero homo hetero homo hetero

Pt.1 + + + multiple

Pt.2 + multiple

Pt.3 + + multiple

Pt.4 + multiple

Pt.5 + + isolated

controls 1.5% 22% 38% 48% 31% 64%


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MR αENaC Target organ

I180V A241V T663A

homo hetero homo hetero homo hetero

controls + + +

controls + +

controls + +

(From reference 106, with permission)

We also identified, in a Japanese patient with sporadic PHA, three homozygous substitutions in the MR gene: G215C, I180V or A241V,which had previously reported to occur in healthy populations. Luciferase activities induced by MR with either G215C, I180V orA241V substitution were significantly lower than those for wild-type MR with aldosterone at concentrations ranging from 10-11 to 10-9M, 10-8M, or 10-11 to 10-6M, respectively. A homozygous A to G substitution of the donor splice site of αENaC intron 4 was found inthe patient. These results suggest that each of three MR polymorphisms identified in our patient is functionally and structurallyheterogeneous (111.1).

We cannot rule out the possibility that the above polymorphisms may confer vulnerability in salt conservation, which might beexpressed fully only when concurrently present with other genetic defects of the MR or other proteins that participate in sodiumhomeostasis, such as Nedd4 (112). Our hypothesis, if true, would be compatible with a sporadic presentation or a digenic or multigenicexpression and heredity as previously described in retinitis pigmentosa (113). In this case, hereditary transmission might be complex andappear either as a dominant and/or recessive trait with variable penetrance.

SECONDARY HYPOALDOSTERONISM (PHA): Clinical PresentationSecondary PHA is a form of renal resistance to aldosterone. The cause of secondary PHA is either renal disease or medication. Theclinical and laboratory findings resemble those to a transient PHA. Since Rodriguez-Soriano et al .reported the first case in 1983 (114),more than 68 cases have been reported (115). Secondary PHA may occur mainly in neonates and young infants with urinary tractinfections, such as pyelonephritis, and/or malformation of urinary system causing obstructive uropathy. This state occurs in male infantsmore frequently than female infants because of the higher incidence of urinary tract infections and obstructive uropathy in male infantsrather than in female infants (115). Patients present poor feeding, poor weight gain or failure to thrive, vomiting, diarrhea, polyuria anddehydration. Acute worsening of their general condition may occur, with severe weight loss, peripheral circulatory failure, rise in serumurea and creatinine levels, and occasional life-threatening hyperkalemia (114,115). The laboratory features are hyponatremia,hyperkalemia, metabolic acidosis, elevation of plasma aldosterone concentrations and plasma renin activity, and inappropriatelyincreased sodium and decreased potassium excretion in urine (115).

PathophysiologyThe very high ratio of plasma aldosterone to potassium, together with diminished urinary K/Na values, strongly suggests thathyponatremia and hyperkalemia result from a lack of response of the renal tubule to endogenous mineralocorticoids (116). Theintrarenal expression of several cytokines, such as tumor necrosis factor a, interleukin (IL) 1,IL-6, transforming growth factor b-1,angiotensin II, endothelin, thromboxane A2, and prostaglandins, is increased in cases of urinary tract infections. These changes result ininhibition of aldosterone action through reduction of its expression and/or impairment of its receptor, vasoconstriction and reduction ofglomerular filtration rate, increased natriuresis and/or decreased Na -K -ATPase activity (115). Kuhnle et al. found that the number ofmineralocorticoid receptors in obstructive uropathy were low in the acute phase but returned to normal after successful surgicalcorrection of the obstruction (117). This suggests that a reduced aldosterone effect can also reflect down-regulation of the receptor sites,due to highly elevated aldosterone levels (117).

TherapyThe clinical and laboratory findings improve within one or two days and disappear after the completion of medical treatment of urinarytract infection and/or surgical correction of obstructive uropathy, usually within a few days to one week after beginning of treatment(115). However, in some patients, sodium bicarbonate and/or sodium chloride supplementation was necessary for a week or month(115).

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