Skip to main content

Advertisement

Log in

Genetics of Salt-Sensitive Hypertension

  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

The assessment of salt sensitivity of blood pressure is difficult because of the lack of universal consensus on definition. Regardless of the variability in the definition of salt sensitivity, increased salt intake, independent of the actual level of blood pressure, is also a risk factor for cardiovascular morbidity and mortality and kidney disease. A modest reduction in salt intake results in an immediate decrease in blood pressure, with long-term beneficial consequences. However, some have suggested that dietary sodium restriction may not be beneficial to everyone. Thus, there is a need to distinguish salt-sensitive from salt-resistant individuals, but it has been difficult to do so with phenotypic studies. Therefore, there is a need to determine the genes that are involved in salt sensitivity. This review focuses on genes associated with salt sensitivity, with emphasis on the variants associated with salt sensitivity in humans that are not due to monogenic causes. Special emphasis is given to gene variants associated with salt sensitivity whose protein products interfere with cell function and increase blood pressure in transgenic mice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Weinberger MH, Fineberg NS, Fineberg SE, et al.: Salt sensitivity, pulse pressure, and death in normal and hypertensive humans. Hypertension 2001, 37:429–432.

    CAS  PubMed  Google Scholar 

  2. •• Strazzullo P, D’Elia L, Kandala NB, et al.: Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies. BMJ 2009, 339:b4567. This article reviews the health-related consequences of increased salt intake.

    Article  PubMed  Google Scholar 

  3. •• He FJ, MacGregor GA: Reducing population salt intake worldwide: from evidence to implementation. Prog Cardiovasc Dis 2010, 52:363–382. This article reviews the health-related consequences of increased salt intake.

    Article  CAS  PubMed  Google Scholar 

  4. Sullivan JM: Salt sensitivity. Definition, conception, methodology, and long-term issues. Hypertension 1991, 17(1 suppl):I61–I68.

    CAS  PubMed  Google Scholar 

  5. Larrousse M, Bragulat E, Segarra M, et al.: Increased levels of atherosclerosis markers in salt-sensitive hypertension. Am J Hypertens 2006, 19:87–93.

    Article  CAS  PubMed  Google Scholar 

  6. Yatabe MS, Yatabe J, Yoneda M, et al.: Salt sensitivity is associated with insulin resistance, sympathetic overactivity, and decreased suppression of circulating renin activity in lean patients with essential hypertension. Am J Clin Nutr 2010, 92:77–82.

    Article  CAS  PubMed  Google Scholar 

  7. de la Sierra A, Giner V, Bragulat E, et al.: Lack of correlation between two methods for the assessment of salt sensitivity in essential hypertension. J Hum Hypertens 2002, 16:255–260.

    Article  PubMed  Google Scholar 

  8. Kawasaki T, Delea CS, Bartter FC, et al.: The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension. Am J Med 1978, 64:193–198.

    Article  CAS  PubMed  Google Scholar 

  9. Kato N, Kanda T, Sagara M, et al.: Proposition of a feasible protocol to evaluate salt sensitivity in a population-based setting. Hypertens Res 2002, 25:801–809.

    Article  PubMed  Google Scholar 

  10. Shore AC, Markandu ND, MacGregor GA: A randomized crossover study to compare the blood pressure response to sodium loading with and without chloride in patients with essential hypertension. J Hypertens 1988, 6:613–617.

    Article  CAS  PubMed  Google Scholar 

  11. Schmidlin O, Forman A, Sebastian A, et al.: Sodium-selective salt sensitivity: its occurrence in blacks. Hypertension 2007, 50:1085–1092.

    Article  CAS  PubMed  Google Scholar 

  12. Kitiyakara C, Chabrashvili T, Chen Y, et al.: Salt intake, oxidative stress, and renal expression of NADPH oxidase and superoxide dismutase. J Am Soc Nephrol 2003, 14:2775–2782.

    Article  CAS  PubMed  Google Scholar 

  13. Oberleithner H, Riethmüller C, Schillers H, et al.: Plasma sodium stiffens vascular endothelium and reduces nitric oxide release. Proc Natl Acad Sci U S A 2007, 104:16281–16286.

    Article  CAS  PubMed  Google Scholar 

  14. Huang BS, Amin MS, Leenen FH: The central role of the brain in salt-sensitive hypertension. Curr Opin Cardiol 2006, 21:295–304.

    Article  PubMed  Google Scholar 

  15. • Pimenta E, Gaddam KK, Oparil S, et al.: Effects of dietary sodium reduction on blood pressure in subjects with resistant hypertension: results from a randomized trial. Hypertension 2009, 54:475–481. This study shows the importance of dietary sodium in resistant hypertension.

    Article  CAS  Google Scholar 

  16. •• Egan BM, Zhao Y, Axon RN: US trends in prevalence, awareness, treatment, and control of hypertension, 1988–2008. JAMA 2010, 303:2043–2050. This is a very important update on essential hypertension in the United States.

  17. Cutler JA, Roccella EJ: Salt reduction for preventing hypertension and cardiovascular disease: a population approach should include children. Hypertension 2006, 48:818–819.

    Article  CAS  PubMed  Google Scholar 

  18. He FJ, MacGregor GA: Importance of salt in determining blood pressure in children: meta-analysis of controlled trials. Hypertension 2006, 48:861–869.

    Article  CAS  PubMed  Google Scholar 

  19. Cohen HW, Alderman MH: Sodium, blood pressure, and cardiovascular disease. Curr Opin Cardiol 2007, 22:306–310.

    Article  PubMed  Google Scholar 

  20. Harsha DW, Sacks FM, Obarzanek E, et al.: Effect of dietary sodium intake on blood lipids: results from the DASH-sodium trial. Hypertension 2004, 43:393–398.

    Article  CAS  PubMed  Google Scholar 

  21. Alderman MH: Dietary sodium and cardiovascular health in hypertensive patients: the case against universal sodium restriction. J Am Soc Nephrol 2004, 15(Suppl 1):S47–S50.

    Article  CAS  PubMed  Google Scholar 

  22. Ruiz-Opazo N, Lopez LV, Tonkiss J: Modulation of learning and memory in Dahl rats by dietary salt restriction. Hypertension 2004, 43:797–802.

    Article  CAS  PubMed  Google Scholar 

  23. Meneton P, Jeunemaitre X, de Wardener HE, et al.: Links between dietary salt intake, renal salt handling, blood pressure, and cardiovascular diseases. Physiol Rev 2005, 85:679–715.

    Article  CAS  PubMed  Google Scholar 

  24. Strazzullo P, Galletti F: Genetics of salt-sensitive hypertension. Curr Hypertens Rep 2007, 9:25–32.

    Article  CAS  PubMed  Google Scholar 

  25. • Logan AG, Friedman O: Can nocturnal hypertension predict cardiovascular risk? Integrated Blood Pressure Control 2009, 2:25–37. This article reviews the role of abnormal salt handling in the pathogenesis of nocturnal hypertension.

    Google Scholar 

  26. O’Brien E: Dipping comes of age. The importance of nocturnal blood pressure. Hypertension 2009, 53:446–447.

    Article  PubMed  CAS  Google Scholar 

  27. Crowley SD, Gurley SB, Herrera MJ, et al.: Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney. Proc Natl Acad Sci USA 2006, 103:17985–17990.

    Article  CAS  PubMed  Google Scholar 

  28. • Asico L, Zhang X, Jiang J, et al.: Cross-transplantation demonstrates regulation of blood pressure by renal dopamine D5 receptors. J Am Soc Nephrol (in press). Mice lacking the D5 dopamine receptor (D 5 R) have increased expression of AT 1 R. Using renal cross-transplantation experiments, Asico et al. show the importance of D 5 R in the kidney in the development of hypertension and show that denervation prevents salt sensitivity in D 5 R knockout mice.

  29. Uzu T, Kimura G: Diuretics shift circadian rhythm of blood pressure from nondipper to dipper in essential hypertension. Circulation 1999, 100:1635–1638.

    CAS  PubMed  Google Scholar 

  30. Lifton RP, Gharavi AG, Geller DS: Molecular mechanisms of human hypertension. Cell 2001, 104:545–556.

    Article  CAS  PubMed  Google Scholar 

  31. Jose PA, Eisner GM, Felder RA: The renal dopamine receptors in health and hypertension. Pharmacol Ther 1998, 80:149–182.

    Article  CAS  PubMed  Google Scholar 

  32. Granger JP, Alexander BT, Llinas M: Mechanisms of pressure natriuresis. Curr Hypertens Rep 2002, 4:152–159.

    Article  PubMed  Google Scholar 

  33. Cowley AW Jr: Renal medullary oxidative stress, pressure-natriuresis, and hypertension. Hypertension 2008, 52:777–786.

    Article  CAS  PubMed  Google Scholar 

  34. Orlov SN, Mongin AA: Salt-sensing mechanisms in blood pressure regulation and hypertension. Am J Physiol Heart Circ Physiol 2007, 293:H2039–H2053.

    Article  CAS  PubMed  Google Scholar 

  35. Bie P: Blood volume, blood pressure and total body sodium: internal signalling and output control. Acta Physiol (Oxf) 2009, 195:187–196.

    Article  CAS  Google Scholar 

  36. • Blaustein MP, Hamlyn JM: Signaling mechanisms that link salt retention to hypertension: endogenous ouabain, the Na+ pump, the Na+/Ca2+ exchanger and TRPC proteins. Biochim Biophys Acta 2010 Mar 6 (Epub ahead of print). This is a review on the role of endogenous ouabain in salt retention and hypertension.

  37. Johnson RJ, Rodriguez-Iturbe B, Kang D, et al.: A unifying pathway for essential hypertension. Am J Hypertens 2005, 18:431–440.

    Article  PubMed  Google Scholar 

  38. Beeks E, Kessels AG, Kroon AA, et al.: Genetic predisposition to salt-sensitivity: a systematic review. J Hypertens 2004, 22:1243–1249.

    Article  CAS  PubMed  Google Scholar 

  39. Kobori H, Nangaku M, Navar LG, Nishiyama A: The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Physiol Rev 2007, 59:251–287.

    CAS  Google Scholar 

  40. Varagic J, Trask AJ, Jessup JA, et al.: New angiotensins. J Mol Med 2008, 86:663–671.

    Article  CAS  PubMed  Google Scholar 

  41. Padia SH, Kemp BA, Howell NL, et al.: Conversion of renal angiotensin II to angiotensin III is critical for AT2 receptor-mediated natriuresis in rats. Hypertension 2008, 51:460–465.

    Article  CAS  PubMed  Google Scholar 

  42. Salomone LJ, Howell NL, McGrath HE, et al.: Intrarenal dopamine D1-like receptor stimulation induces natriuresis via an angiotensin type-2 receptor mechanism. Hypertension 2007, 49:155–161.

    Article  CAS  PubMed  Google Scholar 

  43. Caprioli J, Mele C, Mossali C, et al.: Polymorphisms of EDNRB, ATG, and ACE genes in salt-sensitive hypertension. Can J Physiol Pharmacol 2008, 86:505–510.

    Article  CAS  PubMed  Google Scholar 

  44. Zhang L, Miyaki K, Araki J, et al.: Interaction of angiotensin I-converting enzyme insertion-deletion polymorphism and daily salt intake influences hypertension in Japanese men. Hypertens Res 2006, 29:751–758.

    Article  CAS  PubMed  Google Scholar 

  45. Poch E, Gonzalez D, Giner V, et al.: Molecular basis of salt sensitivity in human hypertension. Evaluation of renin-angiotensin-aldosterone system gene polymorphisms. Hypertension 2001, 38:1204–1209.

    CAS  Google Scholar 

  46. Katsuya T, Ishikawa K, Sugimoto K, et al.: Salt sensitivity of Japanese from the viewpoint of gene polymorphism. Hypertens Res 2003, 26:521–525.

    Article  PubMed  Google Scholar 

  47. Mangrum AJ, Gomez RA, Norwood VF: Effects of AT1A receptor deletion on blood pressure and sodium excretion during altered dietary salt intake. Am J Physiol Renal Physiol 2002, 283:F447–F453.

    CAS  PubMed  Google Scholar 

  48. Gu D, Kelly TN, Hixson JE, et al.: Genetic variants in the renin-angiotensin-aldosterone system and salt sensitivity of blood pressure. J Hypertens 2010, 28:1210–1220.

    CAS  PubMed  Google Scholar 

  49. Pinto V, Pinho MJ, Hopfer U, et al.: Oxidative stress and the genomic regulation of aldosterone-stimulated NHE1 activity in SHR renal proximal tubular cells. Mol Cell Biochem 2008, 310:191–201.

    Article  CAS  PubMed  Google Scholar 

  50. Trochen N, Ganapathipillai S, Ferrari P, et al.: Low prevalence of nonconservative mutations of serum and glucocorticoid-regulated kinase (SGK1) gene in hypertensive and renal patients. Nephrol Dial Transplant 2004, 19:2499–2504.

    Article  CAS  PubMed  Google Scholar 

  51. Rao AD, Sun B, Hopkins P, et al.: Polymorphisms in the serum- and glucocorticoid-inducible kinase 1 genes are associated with blood pressure and renin response to dietary salt intake in humans [abstract]. Presented at the High Blood Pressure Council Research 2010 Scientific Sessions. Washington, DC; October 13–16, 2010.

  52. Alikhani-Koupaei R, Fouladkou F, Fustier P, et al.: Identification of polymorphisms in the human 11beta-hydroxysteroid dehydrogenase type 2 gene promoter: functional characterization and relevance for salt sensitivity. FASEB J 2007, 21:3618–3622.

    Article  CAS  PubMed  Google Scholar 

  53. Thompson EE, Kuttab-Boulos H, Witonsky D, et al.: CYP3A variation and the evolution of salt-sensitivity variants. Am J Hum Genet 2004, 75:1059–1069.

    Article  CAS  PubMed  Google Scholar 

  54. Eap CB, Bochud M, Elston RC, et al.: CYP3A5 and ABCB1 genes influence blood pressure and response to treatment, and their effect is modified by salt. Hypertension 2007, 49:1007–1014.

    Article  CAS  PubMed  Google Scholar 

  55. Zhang L, Miyaki K, Wang W, et al.: CYP3A5 polymorphism and sensitivity of blood pressure to dietary salt in Japanese men. J Hum Hypertens 2010, 24:345–350.

    Article  CAS  PubMed  Google Scholar 

  56. Osborn JW, Fink GD, Sved AF, et al.: Circulating angiotensin II and dietary salt: converging signals for neurogenic hypertension. Curr Hypertens Rep 2007, 9:228–235.

    Article  CAS  PubMed  Google Scholar 

  57. Weber CS, Thayer JF, Rudat M, et al.: Salt-sensitive men show reduced heart rate variability, lower norepinephrine and enhanced cortisol during mental stress. J Hum Hypertens 2008, 22:423–431.

    Article  CAS  PubMed  Google Scholar 

  58. Rao F, Zhang K, Zhang L, et al.: Human tyrosine hydroxylase natural allelic variation: influence on autonomic function and hypertension. Cell Mol Neurobiol 2010 Jun 23 (Epub ahead of print).

  59. Pojoga L, Kolatkar NS, Williams JS, et al.: β-2 adrenergic receptor diplotype defines a subset of salt-sensitive hypertension. Hypertension 2006, 48:892–900.

    Article  CAS  PubMed  Google Scholar 

  60. Gu D, Su S, Ge D, et al.: Association study with 33 single-nucleotide polymorphisms in 11 candidate genes for hypertension in Chinese. Hypertension 2006, 47:1147–1154.

    Article  CAS  PubMed  Google Scholar 

  61. Bengra C, Mifflin TE, Khripin Y, et al.: Genotyping of essential hypertension single-nucleotide polymorphisms by a homogeneous PCR method with universal energy transfer primers. Clin Chem 2002, 48:2131–2140.

    CAS  PubMed  Google Scholar 

  62. Sayk F, Heutling D, Dodt C, et al.: Sympathetic function in human carriers of melanocortin-4 receptor gene mutations. J Clin Endocrinol Metab 2010, 95:1998–2002.

    Article  CAS  PubMed  Google Scholar 

  63. Greenfield JR, Miller JW, Keogh JM, et al.: Modulation of blood pressure by central melanocortinergic pathways. N Engl J Med 2009, 360:44–52.

    Article  CAS  PubMed  Google Scholar 

  64. Tallam LS, Stec DE, Willis MA, et al.: Melanocortin-4 receptor-deficient mice are not hypertensive or salt-sensitive despite obesity, hyperinsulinemia, and hyperleptinemia. Hypertension 2005, 46:326–332.

    Article  CAS  PubMed  Google Scholar 

  65. Dahlberg J, Nilsson LO, von Wowern F, Melander O: Polymorphism in NEDD4L is associated with increased salt sensitivity, reduced levels of P-renin and increased levels of Nt-proANP. PLoS One 2007, 2(5):e432.

    Article  PubMed  CAS  Google Scholar 

  66. Manunta P, Lavery G, Lanzani C, et al.: Physiological interaction between α-adducin and WNK1-NEDD4L pathways on sodium-related blood pressure regulation. Hypertension 2008, 52:366–372.

    Article  CAS  PubMed  Google Scholar 

  67. Rubera I, Loffing J, Palmer LG, et al.: Collecting duct-specific gene inactivation of αENaC in the mouse kidney does not impair sodium and potassium balance. J Clin Invest 2003, 112:554–565.

    CAS  PubMed  Google Scholar 

  68. Marques FZ, Campain AE, Yang YH, et al.: Meta-analysis of genome-wide gene expression differences in onset and maintenance phases of genetic hypertension. Hypertension 2010, 56:319–324.

    Article  CAS  PubMed  Google Scholar 

  69. Bagos PG, Elefsinioti AL, Nikolopoulos GK, et al.: The GNB3 C825T polymorphism and essential hypertension: a meta-analysis of 34 studies including 14,094 cases and 17,760 controls. J Hypertens 2007, 25:487–500.

    Article  CAS  PubMed  Google Scholar 

  70. Martín DN, Andreu EP, Ramírez Lorca R, et al.: G-protein beta-3 subunit gene C825T polymorphism: influence on plasma sodium and potassium concentrations in essential hypertensive patients. Life Sci 2005, 77:2879–2886.

    Article  PubMed  CAS  Google Scholar 

  71. Turner ST, Schwartz GL, Chapman AB, et al.: C825T polymorphism of the G protein beta(3)-subunit and antihypertensive response to a thiazide diuretic. Hypertension 2001, 37(2 Part 2):739–743.

    Google Scholar 

  72. Kelly TN, Rice TK, Gu D, et al.: Novel genetic variants in the α-adducin and guanine nucleotide binding protein beta-polypeptide 3 genes and salt sensitivity of blood pressure. Am J Hypertens 2009, 22:985–992.

    Article  CAS  PubMed  Google Scholar 

  73. Barlassina C, Dal Fiume C, Lanzani C, et al.: Common genetic variants and haplotypes in renal CLCNKA gene are associated to salt-sensitive hypertension. Hum Mol Genet 2007, 16:1630–1638.

    Article  CAS  PubMed  Google Scholar 

  74. Nishi A, Eklof AC, Bertorello AM, et al.: Dopamine regulation of renal Na+, K+-ATPase activity is lacking in Dahl salt-sensitive rats. Hypertension 1993, 21:767–771.

    CAS  PubMed  Google Scholar 

  75. Efendiev R, Krmar RT, Ogimoto G, et al.: Hypertension-linked mutation in the adducin alpha-subunit leads to higher AP2-mu2 phosphorylation and impaired Na+,K+-ATPase trafficking in response to GPCR signals and intracellular sodium. Circ Res 2004, 95:1100–1108.

    Article  CAS  PubMed  Google Scholar 

  76. Torielli L, Tivodar S, Montella RC, et al.: α-Adducin mutations increase Na/K pump activity in renal cells by affecting constitutive endocytosis: implications for tubular Na reabsorption. Am J Physiol Renal Physiol 2008, 295:F478–F487.

    Article  CAS  PubMed  Google Scholar 

  77. Wang R, Zhong B, Liu Y, Wang C: Association between α-adducin gene polymorphism (Gly460Trp) and genetic predisposition to salt sensitivity: a meta-analysis. J Appl Genet 2010, 51:87–94.

    Article  CAS  PubMed  Google Scholar 

  78. Manunta P, Maillard M, Tantardini C, et al.: Relationships among endogenous ouabain, alpha-adducin polymorphisms and renal sodium handling in primary hypertension. J Hypertens 2008, 26:914–920.

    Article  CAS  PubMed  Google Scholar 

  79. Fava C, Montagnana M, Almgren P, et al.: Association between adducin-1 G460W variant and blood pressure in Swedes is dependent on interaction with body mass index and gender. Am J Hypertens 2007, 20:981–989.

    Article  CAS  PubMed  Google Scholar 

  80. Wang JG, Liu L, Zagato L, et al.: Blood pressure in relation to three candidate genes in a Chinese population. J Hypertens 2004, 22:937–944.

    Article  CAS  PubMed  Google Scholar 

  81. Stenström K, Takemori H, Bianchi G, et al.: Blocking the salt-inducible kinase 1 network prevents the increases in cell sodium transport caused by a hypertension-linked mutation in human α-adducin. J Hypertens 2009, 27:2452–2457.

    Article  PubMed  CAS  Google Scholar 

  82. Tikhonoff V, Kuznetsova T, Stolarz K, et al.: β-Adducin polymorphisms, blood pressure, and sodium excretion in three European populations. Am J Hypertens 2003, 16:840–846.

    Article  CAS  PubMed  Google Scholar 

  83. Yoshihara F, Suga S, Yasui N, et al.: Chronic administration of adrenomedullin attenuates the hypertension and increases renal nitric oxide synthase in Dahl salt-sensitive rats. Regul Pept 2005, 128:7–13.

    Article  CAS  PubMed  Google Scholar 

  84. Fujisawa Y, Nagai Y, Miyatake A, et al.: Renal effects of a new member of adrenomedullin family, adrenomedullin2, in rats. Eur J Pharmacol 2004, 497:75–80.

    Article  CAS  PubMed  Google Scholar 

  85. Li Y, Staessen JA, Li LH, et al.: Blood pressure and urinary sodium excretion in relation to the A-1984 G adrenomedullin polymorphism in a Chinese population. Kidney Int 2006, 69:1153–1158.

    Article  CAS  PubMed  Google Scholar 

  86. Banday AA, Lokhandwala MF: Dopamine receptors and hypertension. Curr Hypertens Rep 2008, 10:268–275.

    Article  CAS  PubMed  Google Scholar 

  87. Zeng C, Armando I, Luo Y, et al.: Dysregulation of dopamine-dependent mechanisms as a determinant of hypertension: studies in dopamine receptor knockout mice. Am J Physiol Heart Circ Physiol 2008, 294:H551–H569.

    Article  CAS  PubMed  Google Scholar 

  88. Citarella MR, Choi MR, Gironacci MM, et al.: Urodilatin and dopamine: a new interaction in the kidney. Regul Pept 2009, 153:19–24.

    Article  CAS  PubMed  Google Scholar 

  89. Yao B, Harris RC, Zhang MZ: Intrarenal dopamine attenuates deoxycorticosterone acetate/high salt-induced blood pressure elevation in part through activation of a medullary cyclooxygenase 2 pathway. Hypertension 2009, 54:1077–1083.

    Article  CAS  PubMed  Google Scholar 

  90. Kirchheimer C, Mendez CF, Acquier A, et al.: Role of 20-HETE in D1/D2 dopamine receptor synergism resulting in the inhibition of Na+-K+-ATPase activity in the proximal tubule. Am J Physiol Renal Physiol 2007, 292:F1435–F1442.

    Article  CAS  PubMed  Google Scholar 

  91. Yu C, Yang Z, Ren H, et al.: D3 dopamine receptor regulation of ETB receptors in renal proximal tubule cells from WKY and SHRs. Am J Hypertens 2009, 22:877–883.

    Article  CAS  PubMed  Google Scholar 

  92. Zeng C, Han Y, Huang H, et al.: D1-like receptors inhibit insulin-induced vascular smooth muscle cell proliferation via down-regulation of insulin receptor expression. J Hypertens 2009, 27:1033–1041.

    Article  CAS  PubMed  Google Scholar 

  93. Venkatakrishnan U, Chen C, Lokhandwala MF: The role of intrarenal nitric oxide in the natriuretic response to dopamine-receptor activation. Clin Exp Hypertens 2000, 22:309–324.

    Article  CAS  PubMed  Google Scholar 

  94. Crambert S, Sjöberg A, Eklöf AC, et al.: Prolactin and dopamine 1-like receptor interaction in renal proximal tubular cells. Am J Physiol Renal Physiol 2010, 299:F49–F54.

    Article  CAS  PubMed  Google Scholar 

  95. Khan F, Spicarová Z, Zelenin S, et al.: Negative reciprocity between angiotensin II type 1 and dopamine D1 receptors in rat renal proximal tubule cells. Am J Physiol Renal Physiol 2008, 295:F1110–F1116.

    Article  CAS  PubMed  Google Scholar 

  96. Li H, Armando I, Yu P, et al.: Dopamine 5 receptor mediates Ang II type 1 receptor degradation via a ubiquitin-proteasome pathway in mice and human cells. J Clin Invest 2008, 118:2180–2189.

    Article  CAS  PubMed  Google Scholar 

  97. • Jose PA, Soares-da-Silva P, Eisner GM, Felder RA: Dopamine and G protein-coupled receptor kinase 4 in the kidney: role in blood pressure regulation. Biochim Biophys Acta 2010 Feb 12 (Epub ahead of print). This article reviews the role of GRK4 gene variants in regulating blood pressure.

  98. Olsen NV: Effects of dopamine on renal haemodynamics tubular function and sodium excretion in normal humans. Dan Med Bull 1998, 45:282–297.

    CAS  PubMed  Google Scholar 

  99. O’Connell DP, Ragsdale NV, Boyd DG, et al.: Differential human renal tubular responses to dopamine type 1 receptor stimulation are determined by blood pressure status. Hypertension 1997, 29(1 Pt 1):115–122.

    PubMed  Google Scholar 

  100. Hussain T, Abdul-Wahab R, Kotak DK, et al.: Bromocriptine regulates angiotensin II response on sodium pump in proximal tubules. Hypertension 1998, 32:1054–1059.

    CAS  PubMed  Google Scholar 

  101. Ueda A, Ozono R, Oshima T, et al.: Disruption of the type 2 dopamine receptor gene causes a sodium-dependent increase in blood pressure in mice. Am J Hypertens 2003, 16:853–858.

    Article  CAS  PubMed  Google Scholar 

  102. Yang Z, Asico LD, Yu P, et al.: D5 dopamine receptor regulation of reactive oxygen species production, NADPH oxidase, and blood pressure. Am J Physiol Regul Integr Comp Physiol 2006, 290:R96–R104.

    CAS  PubMed  Google Scholar 

  103. Staudacher T, Pech B, Tappe M, et al.: Arterial blood pressure and renal sodium excretion in dopamine D3 receptor knockout mice. Hypertens Res 2007, 30:93–101.

    Article  CAS  PubMed  Google Scholar 

  104. Rudberg S, Lemne C, Persson B, et al.: The dopaminuric response to high salt diet in insulin-dependent diabetes mellitus and in family history of hypertension. Pediatr Nephrol 1997, 11:169–173.

    Article  CAS  PubMed  Google Scholar 

  105. Sowers JR, Zemel MB, Zemel P, et al.: Salt sensitivity in blacks. Salt intake and natriuretic substances. Hypertension 1988, 12:485–490.

    CAS  PubMed  Google Scholar 

  106. Damasceno A, Santos A, Serrão P, et al.: Deficiency of renal dopaminergic-dependent natriuretic response to acute sodium load in black salt-sensitive subjects in contrast to salt-resistant subjects. J Hypertens 1999, 17:1995–2001.

    Article  CAS  PubMed  Google Scholar 

  107. Haney M, Ward AS, Foltin RW, et al.: Effects of ecopipam, a selective dopamine D1 antagonist, on smoked cocaine self-administration by humans. Psychopharmacology (Berl) 2001, 155:330–337.

    Article  CAS  Google Scholar 

  108. Banday AA, Lau YS, Lokhandwala MF: Oxidative stress causes renal dopamine D1 receptor dysfunction and salt-sensitive hypertension in Sprague-Dawley rats. Hypertension 2008, 51:367–375.

    Article  CAS  PubMed  Google Scholar 

  109. Staessen JA, Kuznetsova T, Zhang H, et al.: Blood pressure and renal sodium handling in relation to genetic variation in the DRD1 promoter and GRK4. Hypertension 2008, 51:1643–1650.

    Article  CAS  PubMed  Google Scholar 

  110. Felder RA, Sanada H, Xu J, et al.: G protein-coupled receptor kinase 4 gene variants in human essential hypertension. Proc Natl Acad Sci U S A 2002, 99:3872–3877.

    Article  CAS  PubMed  Google Scholar 

  111. Sen S, Nesse R, Sheng L, et al.: Association between a dopamine-4 receptor polymorphism and blood pressure. Am J Hypertens 2005, 18:1206–1210.

    Article  CAS  PubMed  Google Scholar 

  112. Gildea JJ, Shah I, Weiss R, et al.: HK-2 human renal proximal tubule cells as a model for G protein-coupled receptor kinase type 4-mediated dopamine 1 receptor uncoupling. Hypertension 2010, 56:505–511.

    Article  CAS  PubMed  Google Scholar 

  113. Williams SM, Ritchie MD, Phillips JA 3 rd, et al.: Multilocus analysis of hypertension: a hierarchical approach. Hum Hered 2004, 57:28–38.

    Article  PubMed  Google Scholar 

  114. Sanada H, Yatabe J, Midorikawa S, et al.: Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension. Clin Chem 2006, 52:352–360.

    Article  CAS  PubMed  Google Scholar 

  115. Speirs HJ, Katyk K, Kumar NN, et al.: Association of G-protein-coupled receptor kinase 4 haplotypes, but not HSD3B1 or PTP1B polymorphisms, with essential hypertension. J Hypertens 2004, 22:931–936.

    Article  CAS  PubMed  Google Scholar 

  116. Zhu H, Lu Y, Wang X, et al.: The G protein-coupled receptor kinase 4 gene modulates stress-induced sodium excretion in black normotensive adolescents. Pediatr Res 2006, 60:440–442.

    Article  CAS  PubMed  Google Scholar 

  117. Zeng C, Villar VA, Eisner GM, et al.: G protein-coupled receptor kinase 4: role in blood pressure regulation. Hypertension 2008, 51:1449–1455.

    Article  CAS  PubMed  Google Scholar 

  118. Rana BK, Insel PA, Payne SH, et al.: Population-based sample reveals gene-gender interactions in blood pressure in white Americans. Hypertension 2007, 49:96–106.

    Article  CAS  PubMed  Google Scholar 

  119. Lohmueller KE, Wong LJ, Mauney MM, et al.: Patterns of genetic variation in the hypertension candidate gene GRK4: ethnic variation and haplotype structure. Ann Hum Genet 2006, 70:27–41.

    Article  CAS  PubMed  Google Scholar 

  120. Wang CJ, Zhao JB, Xu JL, et al.: [Meta-analysis on the association of G894T polymorphism in endothelial nitric oxide synthase gene and essential hypertension in Chinese population]. Zhonghua Liu Xing Bing Xue Za Zhi 2009, 30:845–849.

    PubMed  Google Scholar 

  121. Moe KT, Lim ST, Wong P, et al.: Association analysis of endothelial nitric oxide synthase gene polymorphism with primary hypertension in a Singapore population. J Hum Hypertens 2006, 20:956–963.

    Article  CAS  PubMed  Google Scholar 

  122. Pereira TV, Rudnicki M, Cheung BM, et al.: Three endothelial nitric oxide (NOS3) gene polymorphisms in hypertensive and normotensive individuals: meta-analysis of 53 studies reveals evidence of publication bias. J Hypertens 2007, 25:1763–1774.

    Article  CAS  PubMed  Google Scholar 

  123. Miyaki K, Tohyama S, Murata M, et al.: Salt intake affects the relation between hypertension and the T-786 C polymorphism in the endothelial nitric oxide synthase gene. Am J Hypertens 2005, 18:1556–1562.

    Article  CAS  PubMed  Google Scholar 

  124. Dengel DR, Brown MD, Ferrell RE, et al.: A preliminary study on T-786 C endothelial nitric oxide synthase gene and renal hemodynamic and blood pressure responses to dietary sodium. Physiol Res 2007, 56:393–401.

    CAS  PubMed  Google Scholar 

  125. Machnik A, Dahlmann A, Kopp C, et al.: Mononuclear phagocyte system depletion blocks interstitial tonicity-responsive enhancer binding protein/vascular endothelial growth factor C expression and induces salt-sensitive hypertension in rats. Hypertension 2010, 55:755–761.

    Article  CAS  PubMed  Google Scholar 

  126. Machnik A, Neuhofer W, Jantsch J, et al.: Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med 2009, 15:545–552.

    Article  CAS  PubMed  Google Scholar 

  127. Roman RJ: P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev 2002, 82:131–185.

    CAS  PubMed  Google Scholar 

  128. Laffer CL, Laniado-Schwartzman M, Wang MH, et al.: 20-HETE and furosemide-induced natriuresis in salt-sensitive essential hypertension. Hypertension 2003, 41:703–708.

    Article  CAS  PubMed  Google Scholar 

  129. Capdevila JH: Regulation of ion transport and blood pressure by cytochrome p450 monooxygenases. Curr Opin Nephrol Hypertens 2007, 16:465–467.

    Article  PubMed  Google Scholar 

  130. Williams JM, Sarkis A, Hoagland KM, et al.: Transfer of the CYP4A region of chromosome 5 from Lewis to Dahl S rats attenuates renal injury. Am J Physiol Renal Physiol 2008, 295:F1764–F1777.

    Article  CAS  PubMed  Google Scholar 

  131. D’Angelo G, Loria AS, Pollock DM, et al.: Endothelin activation of reactive oxygen species mediates stress-induced pressor response in Dahl salt-sensitive prehypertensive rats. Hypertension 2010, 56:282–289.

    Article  PubMed  CAS  Google Scholar 

  132. Gariepy CE, Ohuchi T, Williams SC, et al.: Salt-sensitive hypertension in endothelin-B receptor-deficient rats. J. Clin Invest 2000, 105:925–933.

    Article  CAS  PubMed  Google Scholar 

  133. •• Boesen EI, Pollock JS, Pollock DM: Contrasting effects of intervention with ETA and ETB receptor antagonists in hypertension induced by angiotensin II and high-salt diet. Can J Physiol Pharmacol 2010, 88:802–807. These studies indicate the importance of ET A R signaling in the pathogenesis of this animal model of hypertension and that ET B R may be protective.

    Article  CAS  PubMed  Google Scholar 

  134. Bellini C, Ferri C, Piccoli A, et al.: The influence of salt sensitivity on the blood pressure response to exogenous kallikrein in essential hypertensive patients. Nephron 1993, 65:28–35.

    Article  CAS  PubMed  Google Scholar 

  135. Yan JT, Wang T, Li J, et al.: Recombinant adeno-associated virus-mediated human kallikrein gene therapy prevents high-salt diet-induced hypertension without effect on basal blood pressure in rats. Acta Pharmacol Sin 2008, 29:808–814.

    Article  CAS  PubMed  Google Scholar 

  136. Chao J, Zhang JJ, Lin KF, et al.: Human kallikrein gene delivery attenuates hypertension, cardiac hypertrophy, and renal injury in Dahl salt-sensitive rats. Hum Gene Ther 1998, 9:21–31.

    Article  CAS  PubMed  Google Scholar 

  137. Cervenka L, Harrison-Bernard LM, Dipp S, et al.: Early onset salt-sensitive hypertension in bradykinin B2 receptor null mice. Hypertension 1999, 34:176–180.

    CAS  PubMed  Google Scholar 

  138. Newton-Cheh C, Larson MG, Vasan RS, et al.: Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure. Nat Genet 2009, 41:348–353.

    Article  CAS  PubMed  Google Scholar 

  139. Rubattu S, Evangelista A, Barbato D, et al.: Atrial natriuretic peptide (ANP) gene promoter variant and increased susceptibility to early development of hypertension in humans. J Hum Hypertens 2007, 21:822–824.

    Article  CAS  PubMed  Google Scholar 

  140. Schorr U, Beige J, Ringel J, et al.: Hpa II polymorphism of the atrial natriuretic peptide gene and the blood pressure response to salt intake in normotensive men. J Hypertens 1997, 15:715–718.

    Article  CAS  PubMed  Google Scholar 

  141. Glazier AM, Nadeau JH, Aitman TJ: Finding genes that underlie complex traits. Science 2002, 298:2345–2349.

    Article  CAS  PubMed  Google Scholar 

  142. Abiola O, Angel JM, Avner P, et al.; Complex Trait Consortium: The nature and identification of quantitative trait loci: a community’s view. Nat Rev Genet 2003, 4:911–916.

    PubMed  Google Scholar 

Download references

Disclosure

Conflicts of Interest: H. Sanada: none; J.E. Jones: none; P.A. Jose: Board membership and stock ownership in Hypogen, Inc., which owns the patent for GRK4; grants NHLBI-R37HL02308 (GRK4 and development of salt sensitivity) and NHLBI-R02HL092196 (Renal dopamine receptor regulation and function).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Pedro A. Jose.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sanada, H., Jones, J.E. & Jose, P.A. Genetics of Salt-Sensitive Hypertension. Curr Hypertens Rep 13, 55–66 (2011). https://doi.org/10.1007/s11906-010-0167-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-010-0167-6

Keywords

Navigation