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Aldosterone-related genetic effects in hypertension

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Abstract

Our basic understanding of Na+ transport mechanisms provides unique insights into epithelial transport processes. Unusual clinical syndromes can arise from mutations of these ion transporters. These genetic disorders affect Na+ balance, resulting in both Na+ retaining and Na+ wasting conditions. A major focus has been the epithelial sodium channel (ENaC), which can be activated by mutations (eg, Liddle’s syndrome), changes in the response to mineralocorticoids (apparent mineralocorticoid excess syndrome), or production of mineralocorticoids (glucocorticoid-remediable aldosteronism). As a result, we now have clearly defined Mendelian syndromes in which ENaC activity is "dysregulated." This dysregulation leads to systemic hypertension associated with suppressed plasma renin activity, which can be attributed to a primary renal mechanism. Applying these insights to the far more common disorder of low-renin hypertension may shed new light on the underlying pathophysiology of this common form of human hypertension.

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References and Recommended Reading

  1. Guyton AC: Blood pressure control: special role of kidneys and body fluids. Science 1991, 252:1813–1816.

    Article  PubMed  CAS  Google Scholar 

  2. Scheinman SJ, Guay-Woodford L M, Thakker RV, et al.: Genetic disorders of renal electrolyte transport. N Engl J Med 1999, 340:1177–1187. This recent review is authoratative and trenchant, and it provides an extensive listing of renal tubule transport disorders with relevant links to the On-Line Mendelian Inheritance in Man.

    Article  PubMed  CAS  Google Scholar 

  3. Shimkets RA, Warnock DG, Bositis CM, et al.: Liddle’s syndrome: heritable human hypertension caused by mutations in the β subunit of the epithelial sodium channel. Cell 1994, 79:407–414.

    Article  PubMed  CAS  Google Scholar 

  4. Jeunemaitre X, Bassilana F, Persu A, et al.: Genotype-phenotype analysis of a newly discovered family with Liddle’s syndrome. J Hypertens 1997, 15:1091–1100.

    Article  PubMed  CAS  Google Scholar 

  5. Abriel H, Loffing H, Rebhus JF, et al.: Defective regulation of the epithelial Na+ channel by NEDD4 in Liddle’s syndrome. J Clin Invest 1999, 103:667–673. Elegant, definitive studies of the binding interactions between NEDD4 and the ENaC subunits.

    PubMed  CAS  Google Scholar 

  6. Hansson JH, Schild L, Lu Y, et al.: A de novo missense mutation of the β subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity. Proc Natl Acad Sci U S A 1995, 92:11495–11499.

    Article  PubMed  CAS  Google Scholar 

  7. Tamura H, Schild L, Enomoto N, et al.: Liddle disease caused by a missense mutation of β subunit of the epithelial sodium channel gene. J Clin Invest 1996, 97:1780–1784.

    PubMed  CAS  Google Scholar 

  8. Liddle GW, Bledsoe T, Coppage WS: A familial renal disorder simulating primary aldosteronism but with negligible aldosterone secretion. Trans Am Assoc Physicians 1963, 76:199–213.

    CAS  Google Scholar 

  9. Gadallah MF, Abreo K, Work J: Liddle’s syndrome: an under-recognized entity; a report of four cases including the first report in black individuals. Am J Kidney Dis 1995, 25:924–927.

    Google Scholar 

  10. Persu A, Barbry P, Bassilana F, et al.: Genetic analysis of the b subunit of the epithelial Na+ channel in essential hypertension. Hypertension 1998, 32:129–137.

    PubMed  CAS  Google Scholar 

  11. Schild L, Canessa CM, Shimkets RA, et al.: A mutation in the epithelial sodium channel causing Liddle disease increases channel activity in the Xenopus laevis oocyte expression sytem. Proc Natl Acad Sci U S A 1995, 92:5699–5703.

    Article  PubMed  CAS  Google Scholar 

  12. Su YR, Rutkowski MP, Klanke CA, et al.: A novel variant of the β -subunit of the amiloride-sensitive sodium channel in African Americans. J Am Soc Nephrol 1996, 7:2543–2549.

    PubMed  CAS  Google Scholar 

  13. Bubien JK, Jope RS, Warnock DG: G-proteins modulate amiloride-sensitive sodium channels. J Biol Chem 1994, 269:17780–17783.

    PubMed  CAS  Google Scholar 

  14. Oh Y, Warnock DG: Expression of the amiloride-sensitive sodum channel β subunit gene in human β lymphocytes. J Am Soc Nephrol 1997, 8:126–129.

    PubMed  CAS  Google Scholar 

  15. Cui Y, Su YR, Rutkowski M, et al.: Loss of protein kinase C inhibition in the β -T594M variant of the amiloride-sensitive Na+ channel. Proc Natl Acad Sci U S A 1997, 94:9962–9966.

    Article  PubMed  CAS  Google Scholar 

  16. Warnock DG: Editorial: polymorphism in the beta subunit and Na+ transport. J Am Soc Nephrol 1996, 7:2490–2494.

    PubMed  CAS  Google Scholar 

  17. Baker EH, Dong YB, Sagnella GA, et al.: Association of hypertension with T594M mutation in the β subunit of epithelial sodium channels in black people resident in London. Lancet 1998, 351:1388–1392.

    Article  PubMed  CAS  Google Scholar 

  18. Baker EH, Dong YB, Sagnella GA, et al.: T594M mutation in the ENaC beta subunit and low-renin hypertension in blacks: author’s reply. Am J Kidney Dis 1999, 34:583–587. Lively discussion of the case-control studies that demonstrated the association of the β subunit M594T mutation and low-renin hypertension in persons of African ancestry.

    Google Scholar 

  19. Warnock D: T594M mutation in the ENaC beta subunit and low-renin hypertension in blacks: journal club. Am J Kidney Dis 1999, 34:579–587. Editorial comment on Baker et al. [18•].

    PubMed  CAS  Google Scholar 

  20. Ambrosius WT, Bloem LJ, Zhou L, et al.: Genetic variants in the epithelial sodium channel in relation to aldosterone and potassium excretion and risk for hypertension. Hypertension 1999, 34:631–637. Surperb study of the relations among plasma renin, aldosterone, and ENaC polymorphisms. Examines the urinary aldosterone-potassium excretory ratio as a surrogate marker for ENaC activation in humans.

    PubMed  CAS  Google Scholar 

  21. Blackwood A, Baker EH, Dong YB, et al.: The T594M mutation in the β subunit of amiloride-sensitive sodium channel is associated with increased levels of urinary calcium excretion. Hypertension 1998, 32:10.

    Google Scholar 

  22. Botero-Velez M, Curtis JJ, Warnock DG: Brief report: Liddle’s syndrome revisited. N Engl J Med 1994, 330:178–181.

    Article  PubMed  CAS  Google Scholar 

  23. Griffing GT, Wilson TE, Melby JC: Alterations in aldosterone secretion and metabolism in low renin hypertension. J Clin Endocrinol Metab 1990, 71:1454–1460.

    Article  PubMed  CAS  Google Scholar 

  24. Paillard F, Chansel D, Brand E, et al.: Genotype-phenotype relationships for the renin-angiotensin-aldosterone system in a normal population. Hypertension 1999, 34:423–429.

    PubMed  CAS  Google Scholar 

  25. Fisher ND, Gleason RE, Moore TJ, et al.: Regulation of aldosterone secretion in hypertensive blacks. Hypertension 1994, 23:179–184.

    PubMed  CAS  Google Scholar 

  26. Warnock DG: The epithelial sodium channel in hypertension. Curr Hypertens Rep 1999, 1:158–163. Reports global suppression of urinary 18-hyrdroxylase metabolite excretion in patients with Liddle’s syndrome.

    PubMed  CAS  Google Scholar 

  27. Shackleton CH: Mass spectrometry in the diagnosis of steroid-related disorders and in hypertension research. J Steroid Biochem Molec Biol 1993, 45:127–140.

    Article  PubMed  CAS  Google Scholar 

  28. Fisher NDL, Hurwitz S, Ferri C, et al.: Altered adrenal sensitivity to angiotensin II in low-renin essential hypertension. Hypertension 1999, 34:388–394. On closer examination, "nonmodulating" essential hypertension appears to have suppressed adrenal 18-hydroxylase activity related to chronic volume expansion despite "normal" nonsuppressed plasma renin activity.

    PubMed  CAS  Google Scholar 

  29. Warnock DG: Liddle syndrome: an autosomal dominant form of human hypertension. Kidney Int 1998, 53:18–24.

    Article  PubMed  CAS  Google Scholar 

  30. Warnock DG: Low-renin and nonmodulating essential hypertension. Hypertension 1999, 34:395–397. Editorial comment on Fisher et al. [28•].

    PubMed  CAS  Google Scholar 

  31. Geller DS, Rodriquez-Soriano J, Boado AV, et al.: Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism, type I. Nature Genet 1998, 19:279–281.

    Article  PubMed  CAS  Google Scholar 

  32. Geller DS, Farhi A, Moritz M, et al.: A new Mendelian form of human hypertension caused by an activating mutation in the mineralocorticoid receptor [abstract]. J Am Soc Nephrol 1999, 10:345A.

    Article  Google Scholar 

  33. Pratt JH, Rebhun JF, Zhou L, et al.: Levels of mineralocorticoids in whites and blacks. Hypertension 1999, 34:315–319.

    PubMed  CAS  Google Scholar 

  34. Komiya I, Yamada T, Aizawa T, et al.: Inappropriate elevation of the aldosterone/plasma renin activity ratio in hypertensive patients and 18-hydroxy-11-deoxycorticosterone: a subtype of essential hypertension? Cardiology 1991, 78:99–110.

    Article  PubMed  CAS  Google Scholar 

  35. Mune T, Rogerson FM, Nikkila H, et al.: Human hypertension caused by mutations in the kidney isozyme of 11 betahydroxysteroid dehydrogenase. Nature Genet 1995, 10:394–399.

    Article  PubMed  CAS  Google Scholar 

  36. Wilson RC, Krozowski ZS, Li K, et al.: A mutation in the HSD11B2 gene in a family with apparent mineralocorticoid excess. J Clin Endocrinol Metab 1995, 80:2263–2266.

    Article  PubMed  CAS  Google Scholar 

  37. Funder JW, Pearce PT, Smith AT: Mineralocorticoid action: target tissue specificity is enzyme, not receptor mediated. Science 1987, 242:583–585.

    Article  Google Scholar 

  38. Stewart PM, Valentino R, Wallace AM, et al.: Mineralocorticoid activity of liquorice: 11b-hydroxysteroid dehydrogenase deficiency comes of age. Lancet 1987, 2:821–824.

    Article  PubMed  CAS  Google Scholar 

  39. Lee YS, Lorenzo BJ, Koufis T, et al.: Grapefruit juice and its flavonoids inhibit 11b-hydroxysteroid dehydrogenase. Clin Pharmacol Ther 1996, 59:62–71.

    Article  PubMed  CAS  Google Scholar 

  40. Edwards DJ, Bernier SM: Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice. Life Sci 1996, 59:1025–1030.

    Article  PubMed  CAS  Google Scholar 

  41. Ingram MC, Wallace AM, Collier A, et al.: Sodium status, corticosteroid metabolism and blood pressure in normal human subjects and in a patient with abnormal salt appetite. Clin Exp Pharmacol Physiol 1996, 23:375–378.

    PubMed  CAS  Google Scholar 

  42. Soro A, Ingram MC, Tonolo G, et al.: Evidence of coexisting changes in 11b-hydroxysteroid dehydrogenase and 5b reductase activity in subjects with untreated essential hypertension. Hypertension 1995, 25:67–70.

    PubMed  CAS  Google Scholar 

  43. Walker BR, Stewart PM, Shackleton CHL, et al.: Deficient inactivation of cortisol by 11b-hydroxysteroid dehydrogenase in essential hypertension. Clin Endocrinol 1993, 39:221–227.

    CAS  Google Scholar 

  44. Lovati E, Ferrari P, Dick B, et al.: Molecular basis of human salt sensitivity: the role of the 11beta-hydroxysteroid dehydrogenase type 2. J Clin Endocrinol Metab 1999, 84:3745–3749. Although 11b-hydroxy steroid dehydrogenase type II activity does not appear to be modulated by dietary salt intake, there may be an effect on systemic hypertension of dietary salt excess related to the 11b-hydroxy steroid dehydrogenase type II genotype.

    Article  PubMed  CAS  Google Scholar 

  45. Watson BJ, Bergman SM, Myracle A, et al.: Genetic association of 11 beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) flanking microsatellites with essential hypertension in blacks. Hypertension 1996, 28:478–482.

    PubMed  CAS  Google Scholar 

  46. Palermo M, Cossu M, Shackleton CHL: Cure of apparent mineralocorticoid excess by kidney transplantation. N Engl J Med 1998, 339:1787–1788. The apparent mineralocorticoid excess syndrome is a renal disorder, like Liddle’s syndrome, that is "cured" by renal transplantation. Urinary excretion of the reduced metabolites of cortisol compared with cortisone may be misleading; measurements of urinary-free cortisol and free cortisone may be more directly relevant to the underlying pathophysiology.

    Article  PubMed  CAS  Google Scholar 

  47. Smolenicka Z, Bach E, Schaer A, et al.: A new polymorphic restriction site in the human 11 beta-hydroxysteroid dehydrogenase type 2 gene. J Clin Endocrin Metabol 1998, 83:1814–1817.

    Article  CAS  Google Scholar 

  48. He FJ, Markandu ND, Sagnella GA, et al.: Importance of the renin system in determining blood pressure fall with salt restriction in black and white hypertensives. Hypertension 1998, 32:820–824.

    PubMed  CAS  Google Scholar 

  49. Bubien JK, Ismailov II, Berdiev BK, et al.: Liddle’s disease: abnormal regulation of amiloride-sensitive Na+ channels by b-subunit mutation. Am J Physiol (Cell Physiol) 1996, 270:C208-C213.

    CAS  Google Scholar 

  50. Baker E, Jeunemaitre X, Portal AJ, et al.: Abnormalities of nasal potential difference measurement in Liddle’s syndrome. J Clin Invest 1998, 102:10–14.

    Article  PubMed  CAS  Google Scholar 

  51. Baker EH, Portal AJ, McElvaney TA, et al.: Epithelial sodium channel activity is not increased in hypertension in whites. Hypertension 1999, 33:1031–1035.

    PubMed  CAS  Google Scholar 

  52. Gadallah MF, Mignone J, Habashi K, et al.: Epithelial sodium channel-dependent hypertension: an emerging syndrome: clinical and hormonal characteristics [abstract]. J Am Soc Nephrol 1999, 10:365A.

    Google Scholar 

  53. Lifton RP: Molecular genetics of human blood pressure variation. Science 1996, 272:676–680.

    Article  PubMed  CAS  Google Scholar 

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  1. Division of Nephrology, University of Alabama at Birmingham, 1530 3rd Avenue South, THT 647, 35294-0007, Birmingham, AL, USA

    David G. Warnock MD

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Warnock, D.G. Aldosterone-related genetic effects in hypertension. Current Science Inc 2, 295–301 (2000). https://doi.org/10.1007/s11906-000-0013-3

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