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• W2076389615 abstract "Several familial forms of hypertension have been identified, in which the mendelian pattern of inheritance indicated that hypertension results from the alteration of a single gene. This short review focuses on those rare monogenic disorders characterized by a low-renin profile. This common feature reflects that the causative mutations responsible for these disorders all result in an excessive sodium reabsorption in the aldosterone-dependent nephron. Low-renin familial hypertensions with hypokalemia encompass familial hyperaldosteronisms, in which aldosterone levels are elevated, and familial pseudohyperaldosteronisms, mimicking aldosteronism despite appropriately suppressed aldosterone levels. In these disorders, the avidity of the kidney for sodium is because of dysregulated sodium reabsorption through the epithelial sodium channel ENaC and results in potassium wasting and metabolic alcalosis. Familial hypertension with hyperkalemia is a specific syndrome resulting from mutations in at least 3 different genes, among which 2 have been recently identified. These genes encode members of a new family of kinase, the WNK kinases, involved in the regulation of sodium and potassium excretion by the kidney. Several familial forms of hypertension have been identified, in which the mendelian pattern of inheritance indicated that hypertension results from the alteration of a single gene. This short review focuses on those rare monogenic disorders characterized by a low-renin profile. This common feature reflects that the causative mutations responsible for these disorders all result in an excessive sodium reabsorption in the aldosterone-dependent nephron. Low-renin familial hypertensions with hypokalemia encompass familial hyperaldosteronisms, in which aldosterone levels are elevated, and familial pseudohyperaldosteronisms, mimicking aldosteronism despite appropriately suppressed aldosterone levels. In these disorders, the avidity of the kidney for sodium is because of dysregulated sodium reabsorption through the epithelial sodium channel ENaC and results in potassium wasting and metabolic alcalosis. Familial hypertension with hyperkalemia is a specific syndrome resulting from mutations in at least 3 different genes, among which 2 have been recently identified. These genes encode members of a new family of kinase, the WNK kinases, involved in the regulation of sodium and potassium excretion by the kidney. Several familial forms of hypertension have been described since the 60s, in which the mendelian pattern of inheritance indicated that hypertension results from the alteration of a single gene. Although rare, these disorders offered the unique opportunity to identify genes centrally involved in the control of blood pressure. Most of these genes have been now characterized and the pathophysiology of the related-disorders comprehensively understood. Except for the unique form of autosomal dominant hypertension associated with bradydactyly, all these mendelian disorders are low-renin forms of hypertension reflecting an excessive sodium reabsorption in the distal part of the nephron as a common underlying mechanism. This review will focus on those inherited disorders resulting in sodium avid states. The most distal part of the nephron in the kidney cortex plays a pivotal role in blood pressure control by adjusting sodium and potassium excretion at a level appropriate for dietary intake. The late distal convoluted tubule; the connecting tubule; and, although to a lesser prominent extent than until recently believed, the cortical collecting duct are centrally involved in the final adjustment of urinary sodium excretion controlled by aldosterone.1Meneton P. Loffing J. Warnock D.G. Sodium and potassium handling by the aldosterone-sensitive distal nephron The pivotal role of the distal and connecting tubule.Am J Physiol Renal Physiol. 2004; 287: F593-F601Crossref PubMed Scopus (163) Google Scholar The adrenal cortex synthetizes from common precursors the circulating glucocorticoids, gonadal hormones, and aldosterone through a series of enzymatic steps, each of those being catalyzed by specific enzymes. Production of glucocorticoids in the zona fasciculata is regulated by corticotropin, whereas aldosterone production in the zona glomerulosa is chiefly controlled by angiotensin II and serum potassium. The functional zonation is the consequence of the fact that corticotropin and angiotensin II specifically control the transcription of the respective key enzymes involved in the synthesis of gluco- and mineralocorticoids. Circulating glucocorticoids and mineralocorticoids exert their action by activating their respective receptors, the glucocorticoid receptor and the mineralocorticoid receptor (MR). In vitro, the affinity of cortisol for the MR is similar to aldosterone, but its circulating levels are by far higher (×100) so that cortisol could act as a mineralocorticoid. In vivo, in the aldosterone targets tissues (the kidney, the colon, and the salivary gland), a cross-activation of the MR by cortisol is prevented by the action of the enzyme 11β-hydroxysteroid dehydrogenase type 2, which converts cortisol into cortisone, which is inactive on MR. In the distal nephron, the rate of transepithelial sodium reabsorption is mainly determined by the activity of the apical amiloride-sensitive sodium channel ENaC, which is controlled by aldosterone. The alternative transport system for sodium, the thiazide sensitive sodium-chloride symport sodium chloride cotransport (NCC), is only present in the distal convoluted tube. The effect of aldosterone on ENaC’s activity relies on the regulation of trafficking of the channels between intracellular compartment and the plasma membrane. Aldosterone controls the insertion or retrieval from the plasma membrane of all 3 subunits of the channel: α, β, and γ Enac.2Snyder P.M. Minireview Regulation of epithelial Na+ channel trafficking.Endocrinology. 2005; 146: 5079-5085Crossref PubMed Scopus (198) Google Scholar The retrieval of ENaC from the membrane is mediated by an interaction of the β or γ subunit cytosolic tail with the cytoskeletal protein Nedd4. Aldosterone potently induces the expression of the serum- and glucocorticoid inducible kinase Sgk1, which phosphorylates Nedd4, resulting in an inhibition of its ability to promote ENaC retrieval from the membrane. Aldosterone thereby positively controls the abundance of functional sodium channels present in the apical membrane. High aldosterone levels also increase the abundance of NCC in the apical membrane, and upregulates Na-K-ATP-ase activity, further enhancing sodium reabsorption capacity. The aldosterone-sensitive distal nephron is also the site of potassium secretion, which occurs through the apical K channel ROMK. High dietary potassium markedly increases ROMK abundance to the membrane. Whether aldosterone directly controls ROMK activity is still unclear, but indirectly, through its effects on ENaC and Na-K-ATP-ase activities, aldosterone stimulates the electrochemical driving force for potassium secretion.3Wang W. Regulation of renal K transport by dietary K intake.Annu Rev Physiol. 2004; 66: 547-569Crossref PubMed Scopus (86) Google Scholar The common feature of the familial forms of arterial hypertension with a low-renin profile reflects that the causative mutations are responsible for excessive sodium reabsorption in the aldosterone-dependent nephron. Increased sodium and subsequent water retention by the kidney expands extracellular fluid volume, resetting cardiac output and blood pressure at a higher level and suppressing endogenous plasma renin activity. The various syndromes can be classified according to the kalemia of the patients. Low-renin familial hypertensions with hypokalemia form an heterogenous group of disorders that include (1) familial hyperaldosteronisms, in which aldosterone levels are elevated, and (2) familial pseudohyperaldosteronisms, mimicking aldosteronism despite appropriately suppressed aldosterone levels. In these disorders, dysregulated sodium reabsorption through ENaC results in potassium wasting and metabolic alkalosis (Table 1) Familial hypertension with hyperkalemia is a specific syndrome resulting from mutations in at least 3 different genes, among which 2 have been recently identified.Table 1Familial Hypertensions with HypokalemiaInheritanceGene(s)MineralocorticoidDiagnosisTreatmentFamilial hyperaldosteronismsLow PRA High plasma aldosterone Glucocorticoid remediable aldosteronismADCYP11B1-CYP11B2 hybrid geneAldosteroneDexamethasone test positive Genetic testDexamethasone, amiloride, spironolactone Hyperaldosteronism type IIADUnknown Mapped to ch 7p22AldosteroneDexamethasone test negative, high plasma 18-oxo and 18-hydroxycortisolSurgery (adenoma) or amiloride/spironolactone (hyperplasia)Familial pseudoaldosteronismsLow PRA Low plasma aldosterone Liddle syndrome (PA-I)ADβ or γ ENaC-Low PRA and plasma aldosterone Genetic testAmiloride (spironolactone ineffective) Hypertension exacerbated by pregnancy (PA-II)ADMineralocorticoid receptor S810L mutationCortisone, progesteroneGenetic testAmiloride (spironolactone contraindicated) Apparent mineralocorticoid excess (Ulick syndrome)ARHSD11B2 inactivating mutationsCortisolIncreased urinary THF/THEAmiloride Congenital adrenal hyperplasiaADCYP17 CYP11B2DeoxycorticosteroneGenetic test hypoandrogenemia hyperandrogenemiaAmiloride Open table in a new tab Familial mineralocorticoid excess is characterized by the association of low-renin hypertension and high aldosterone. They are clinically only distinguishable from primary aldosteronism by the fact that a familial history points to a monogenic disorder. Whereas metabolic alcalosis and hypokalemia is the classical feature, serum potassium in the normal range is not infrequent and aldosterone levels can be normal as well. Therefore, the diagnosis relies on the subnormal plasma aldosterone levels and plasma renin activities after 3 weeks of antihypertensive treatment washout. The ability of dexamethasone to suppress the excess of aldosterone distinguishes 2 types of familial hyperaldosteronisms. Glucocorticoid remediable aldosteronism, first described in 1966,4Sutherland D.J. Ruse J.L. Laidlaw J.C. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone.Can Med Assoc J. 1966; 95: 1109-1119PubMed Google Scholar is an autosomal dominant form of hypertension characterized by a corticotrophin-dependent excess of aldosterone. The molecular basis of this disorder is an hybrid gene resulting from unequal crossing over between 2 genes, CYP11B1 and CYP11B2, during meiosis.5Lifton R.P. Dluhy R.G. Powers M. et al.Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase.Nat Genet. 1992; 2: 66-74Crossref PubMed Scopus (306) Google Scholar These 2 genes respectively encode for the enzyme 11b-hydroxylase that catalyzes the last step in cortisol synthesis and for the aldosterone synthase (18 hydroxylase) that converts corticosterone to aldosterone. The hybrid gene contains the 5′ region of CYP11B1, including the corticotropin responsive promotor and the distal region of CYP11B2 that encodes for the aldosterone synthase activity. As a result, corticotropin induces ectopic aldosterone secretion in the zona fasciculata in a nonregulated fashion because aldosterone has no feedback suppressive effect on corticotropin secretion. The exogenous administration of the glucocorticoid dexamethasone decreases aldosterone secretion and restores a normal regulation of the renin-angiotensin-aldosterone system. The differential diagnosis of familial hyperaldosteronism type I could rely on showing a corticotropin-dependent increased secretion of 18-hydroxy- and 18-oxo metabolites of cortisol and cortisone. The suppression test by dexamethasone is sensitive, but it lacks specificity. A direct genetic screening for the presence of the chimeric gene by polymerase chain reaction is the more reliable test used to diagnose familial hyperaldosteronism type I. Low-dose glucocorticoids (dexamethasone 0.25-0.50 mg daily), amiloride, or spironolactone are effective treatments but often need to be complemented with other antihypertensive agents.6McMahon G.T. Dluhy R.G. Glucocorticoid-remediable aldosteronism.Cardiol Rev. 2004; 12: 44-48Crossref PubMed Scopus (60) Google Scholar The type II form of familial aldosteronism is characterized by the lack of aldosterone suppression by glucocorticoids. An apparent autosomal dominant pattern of inheritance suggests a monogenic basis. The condition is phenotypically and genetically heterogeneous. It is associated with bilateral adrenocortical hyperplasia or aldosterone secreting adenomas, and linkage analysis has shown an association with chromosome region 7p22 in 1 large family, but excluded this locus in others.7So A. Duffy D.L. Gordon R.D. et al.Familial hyperaldosteronism type II is linked to the chromosome 7p22 region but also shows predicted heterogeneity.J Hypertens. 2005; 23: 1477-1484Crossref PubMed Scopus (87) Google Scholar Thus, familial hyperaldosteronism type II is only different from primary aldosteronism by the fact that a familial history suggests a monogenic disorder. Even though diagnosis and treatment are the same as for sporadic aldosterone-producing adenoma or bilateral idiopathic hyperplasia, identifying familial hyperaldosteronsim type II in affected families is of interest because it may increase the chances of success of the research teams currently trying to identify the causative genes. Pseudohyperaldosteronisms are characterized by early-onset, severe low-renin hypertension and hypokalemia, and low aldosterone concentrations. They include a number of well-characterized disorders. This autosomal dominant hypertension, described by Liddle in 1963, is a low-renin, low-aldosterone hypertension with hypokalemia, the prototypic form of pseudohyperaldosteronism.8Liddle G. Bledsoe T. Coppage W.J. A familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion.Trans Assoc Phys. 1963; 76: 199-213Google Scholar The correction of hypertension and hypokalemia after kidney transplantation ruled out a circulating mineralocorticoid as a cause of the disease and pointed to an intrinsic defect within the kidney of the aldosterone-dependent sodium reabsorption pathway.9Botero-Velez M. Curtis J.J. Warnock D.G. Brief report Liddle’s syndrome revisited—A disorder of sodium reabsorption in the distal tubule.N Engl J Med. 1994; 330: 178-181Crossref PubMed Scopus (337) Google Scholar The cloning of the 3 genes encoding for the subunits that form the epithelial sodium channel, α, β, and γ ENaC, identified mutations in either the β or γ subunits as being responsible for the disease. These mutations delete the region of the cytosolic tail of the subunit that interacts with Nedd4, resulting in the loss of normal control of the channel retrieval from the apical membrane.10Warnock D.G. Liddle syndrome Genetics and mechanisms of Na+ channel defects.Am J Med Sci. 2001; 322: 302-307Crossref PubMed Scopus (82) Google Scholar The spontaneous permanent activation of sodium reabsorption via ENaC is sensitive to amiloride or triamterene but not spironolactone. This autosomal dominant condition shares with the other forms of pseudohyperaldosteronism severe early-onset hypertension with low-renin and aldosterone levels. Up to now, it has been described only in 1 unique family.11Geller D.S. Farhi A. Pinkerton N. et al.Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy.Science. 2000; 289: 119-123Crossref PubMed Scopus (562) Google Scholar The disease is caused by a single amino-acid substitution in the hormone-binding domain of the mineralocorticoid receptor (S810L), resulting in changes in its sensitivity and specificity. Cortisone can act as an agonist of the mutated receptor,12Rafestin-Oblin M.E. Souque A. Bocchi B. et al.The severe form of hypertension caused by the activating S810L mutation in the mineralocorticoid receptor is cortisone related.Endocrinology. 2003; 144: 528-533Crossref PubMed Scopus (90) Google Scholar causing hypertension in affected males and females. Furthermore, progesterone has a high affinity for the mutated receptor and functions as a potent agonist, resulting in a very severe exacerbation of hypertension and hypokalemia during pregnancy. Spironolactone is also an agonist of the mutated receptor and is contraindicated as it worsens hypertension. Blockade of sodium entry via ENaC by amiloride is the treatment of choice. Apparent mineralocorticoid excess (AME), described in 1977,13New M.I. Levine L.S. Mineralocorticoid hypertension in childhood.Mayo Clin Proc. 1977; 52: 323-328PubMed Google Scholar also known as the Ulick syndrome, is an autosomal recessive disorder caused by inactivating mutations in the HSD11B2 gene that encodes for the 11 β-hydroxysteroid deshydrogenase type 2.14Mune T. Rogerson F. Nikkila H. et al.Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase.Nat Genet. 1995; 10: 394-399Crossref PubMed Scopus (598) Google Scholar, 15Wilson R. Krozowski Z. Li K. et al.A mutation in the HSD11B2 gene in a family with apparent mineralocorticoid excess.J Clin Endocrinol Metab. 1995; 80: 2263-2266Crossref PubMed Google Scholar Homozygous or compound heterozygous mutations result in ineffective inactivation in the kidney of cortisol, which can exert a potent mineralocorticoid effect. A similar clinical picture to AME may occur after the ingestion of bioflavonoids, licorice, and carbenoxolone, which are competitive inhibitors of 11beta-HSD2. In AME patients, serum cortisol is normal, but the ratio of tetrahydrocortisol to tetrahydrocortisone in the urine is characteristically high. AME is a potentially fatal condition, with very early onset of severe hypertension, profound hypokaliemia, and suppressed renin and aldosterone levels. Nephrocalcinosis is present in most patients. The autosomal recessive pattern of inheritance explain why this condition is particularly rare and mainly only occurs in specific clusters of population in which endogamy favors a founder effect. A few missense mutations have been described with a milder phenotype.16Lavery G.G. Ronconi V. Draper N. et al.Late-onset apparent mineralocorticoid excess caused by novel compound heterozygous mutations in the HSD11B2 gene.Hypertension. 2003; 42: 123-129Crossref PubMed Scopus (52) Google Scholar The treatment relies on the use of spironolactone and amiloride, usually at large doses and in combination with other antihypertensive therapies. Congenital adrenal hyperplasia is a group of autosomal recessive disorders linked to inactivating mutations in genes encoding for enzymes involved in the synthesis of cortisol.17New M. Inborn errors of adrenal steroidogenesis.Mol Cell Endocrinol. 2003; 211: 75-83Crossref PubMed Scopus (114) Google Scholar Mutations in CYP17, the gene encoding for the enzyme 17α-hydroxylase, essential for cortisol synthesis, results in impaired cortisol production with corticotropin-induced excessive 11-deoxycorticosterone and corticosterone levels. In addition, the 17α-hydroxylase has a 17,20-lyase activity, essential for the synthesis of gonadal hormones. The lack of 17,20-lyase activity results in failure of pubertal development in females and undervirilization in males. Mutations in CYP11B1, the gene encoding for 11 β-hydroxylase, also impairs normal production of cortisol, resulting in increased levels of corticotrophin, which, in turn, stimulates the production of cortisol precursors, 11-deoxycortisol (compound S), and 11-deoxycorticosterone, which acts as a potent mineralocorticoid. Because the 17,20 lyase activity is not altered, increased synthesis of cortisol precursors result in hyperandrogenemia. Also referred to as the Gordon syndrome or pseudohypoaldosteronism type 2, this rare autosomal dominant form of low-renin hypertension associated with hyperkalemia and hyperchloremic metabolic acidosis despite normal glomerular filtration rate was first described in 1964.18Paver W. Pauline G. hypertension and hyperpotassaemia without renal disease in a young male.Med J Aust. 1964; 2: 305-306PubMed Google Scholar These features, together with a peculiar sensitivity to thiazide diuretics, have strongly suggested a primary renal defect in the distal part of the nephron as a cause of the syndrome. In contrast with pseudohyperaldosteronism patients, in whom early-onset hypertension is constant but the metabolic disorders are often missing, hyperkalemia is constant in FHH patients since childhood, but hypertension commonly develops in middle adulthood. Genetic linkage has been reported with 3 different loci, which could all be excluded in some other families, indicating that at least 4 different genes can cause the disease.19Disse-Nicodeme S. Achard J.M. Desitter I. et al.A new locus on chromosome 12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant form of hypertension.Am J Hum Genet. 2000; 67: 302-310Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Two of these genes have recently been identified. They encode for 2 members, WNK1 and WNK4, of a novel family of serine/threonine kinases (with no lysine[K]).20Wilson F.H. Disse-Nicodeme S. Choate K.A. et al.Human hypertension caused by mutations in WNK kinases.Science. 2001; 293: 1107-1112Crossref PubMed Scopus (1250) Google Scholar Both gene products have been shown to localize in the distal nephron, confirming this segment as the anatomic and functional origin of FHH syndromes.20Wilson F.H. Disse-Nicodeme S. Choate K.A. et al.Human hypertension caused by mutations in WNK kinases.Science. 2001; 293: 1107-1112Crossref PubMed Scopus (1250) Google Scholar Disease-causing mutations are either hypermorphic mutations in the WNK1 gene or missense mutations in particular segments of the WNK4 gene. The exact underlying pathophysiology of FHH remains unclear.21Hadchouel J. Delaloy C. Faure S. et al.Familial hyperkalemic hypertension.J Am Soc Nephrol. 2006; 17: 208-217Crossref PubMed Scopus (74) Google Scholar Important research efforts in various in vitro experimental models suggest that WNK4 controls NCC retrieval from the plasma membrane and that inactivating mutations of WNK4 results in abnormally high sodium reabsorption via the thiazide sensitive pathway. WNK1 appears to act as an endogenous inhibitor of WNK4 so that increased expression of WNK1 might also result in increased abundance of NCC in the membrane. On the other hand, additional experimental findings suggest that WNK4 regulates the paracellular chloride permeability and that the disease-causing mutations further increase this permeability, thereby favoring sodium reabsorption through ENaC. Together with the low-renin state and the high sensivitivity to diuretics, these findings strongly indicate that excessive sodium chloride reabsorption in the distal nephron is involved in the pathogenesis of these disorders but whether NCC or ENaC or both are involved remains unclear. Likewise, the mechanism impairing potassium secretion is not comprehensively understood. Excessive chloride reabsorption through the paracellular route or accompanied with sodium via NCC would result in a decrease of the lumen-negative potential that drives potassium excretion, but a direct regulatory role of WNK4 on the K channel ROMK abundance in the apical membrane is also supported by experimental data. Finally, it is still not understood why, in contrast to all other inherited sodium avid states, hypertension occurs mainly during adulthood whereas the metabolic disorders are present at birth. Answering these questions by precisely identifying the functions of WNK1 and WNK4 in the regulation of distal ion handling will likely improve our understanding of the complexity of aldosterone-responsive nephron physiology." @default.
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• W2076389615 date "2006-04-01" @default.
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• W2076389615 title "Inherited Sodium Avid States" @default.
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