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Current Hypertension Reports

, Volume 14, Issue 5, pp 468–472 | Cite as

The Kidney and Hypertension: Pathogenesis of Salt-Sensitive Hypertension

  • Tatsuo ShimosawaEmail author
  • Shengyu Mu
  • Shigeru Shibata
  • Toshiro Fujita
Antihypertensive Therapy: Renal Injury (MR Weir and GL Bakris, Section Editors)

Abstract

Salt-sensitive hypertension is closely related with natriuretic capacity of the kidney. Besides several genome-wide research reported candidate gene or gene polymorphism responsible for salt-sensitive hypertension, recently, several new factors for acquired salt-sensitive hypertension are reported. Among them, we have identified that rac1, a small GTPase, activates mineralocorticoid receptor in aldosterone-independent fashion and induces salt-sensitive hypertension in several rodent model. On the other hand, sympathoactivation in the brain and/or kidney regulate sodium handlings in the kidney. Recently it is reported that oxidative stress in the brain or in the kidney may modulate sympathetic tone. Moreover, we reported that β2 adrenoceptor alters histone acetylation and further regulates sodium resorption at distal tubules via activating glucocorticoid receptor. These regulations are to be confirmed in humans and the future, and may open a new door for diagnosis and treatment of salt-sensitive hypertension or moreover preventing development of salt-sensitive hypertension.

Keywords

Hypertension Blood pressure Kidney Renal injury Salt-sensitive hypertension Mineralocorticoid receptor MR rac1 ENaC SgK1 RhoGDI NCC WNK4 Epigenetics Glucocorticoid receptor Oxidative stress Sympathetic nerve β2 adrenoceptor Histone acetylation HDAC8 Angiotensin II Roximal tubule Distal tubule 

Notes

Acknowledgments

This work was supported by grants-in-aid for Scientific Research on Priority Areas from the Japan Society for the Promotion of Science.

Disclosure

T. Shimosawa: none; S. Mu: none; S. Shibata: none; T. Fujita: grant from Japan Society for the Promotion of Science.

References

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

  1. 1.
    Fujita T, Henry W, Bartter F, Lake C, Delea C. Factors influencing blood pressure in salt-sensitive patients with hypertension. Am J Med. 1980;69:334–44.PubMedCrossRefGoogle Scholar
  2. 2.
    Morimoto A, Uzu T, Fujii T, Nishimura M, Kuroda S, Nakamura S, et al. Sodium sensitivity and cardiovascular events in patients with essential hypertension. Lancet. 1997;350:1734–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Guyton AC. Blood pressure control-special role of the kidneys and body fluids. Science. 1991;252:1813–16.PubMedCrossRefGoogle Scholar
  4. 4.
    Sanada H, Jones JE, Jose PA. Genetics of salt-sensitive hypertension. Curr Hypertens Rep. 2011;13:55–66.PubMedCrossRefGoogle Scholar
  5. 5.
    Soundararajan R, Melters D, Shih IC, Wang J, Pearce D. Epithelial sodium channel regulated by differential composition of a signaling complex. Proc Natl Acad Sci U S A. 2009;106:7804–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Diakov A, Korbmacher C. A novel pathway of epithelial sodium channel activation involves a serum- and glucocorticoid-inducible kinase consensus motif in the C terminus of the channel's alpha-subunit. J Biol Chem. 2004;279:38134–42.PubMedCrossRefGoogle Scholar
  7. 7.
    Thomas SV, Kathpalia PP, Rajagopal M, Charlton C, Zhang J, Eaton DC, et al. Epithelial sodium channel regulation by cell surface-associated serum- and glucocorticoid-regulated kinase 1. J Biol Chem. 2011;286:32074–85.PubMedCrossRefGoogle Scholar
  8. 8.
    Ring AM, Cheng SX, Leng Q, Kahle KT, Rinehart J, Lalioti MD, et al. WNK4 regulates activity of the epithelial Na + channel in vitro and in vivo. Proc Natl Acad Sci U S A. 2007;104:4020–24.PubMedCrossRefGoogle Scholar
  9. 9.
    Pearce D, Kleyman TR. Salt, sodium channels, and SGK1. J Clin Invest. 2007;117:592–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Zhang W, Xia X, Reisenauer MR, Rieg T, Lang F, Kuhl D, et al. Aldosterone-induced Sgk1 relieves Dot1a-Af9-mediated transcriptional repression of epithelial Na + channel alpha. J Clin Invest. 2007;117:773–83.PubMedCrossRefGoogle Scholar
  11. 11.
    Soundararajan R, Pearce D, Ziera T. The role of the ENaC-regulatory complex in aldosterone-mediated sodium transport. Mol Cell Endocrinol. 2012;350:242–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17.PubMedCrossRefGoogle Scholar
  13. 13.
    Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21.PubMedCrossRefGoogle Scholar
  14. 14.
    Zennaro MC, Souque A, Viengchareun S, Poisson E, Lombes M. A new human MR splice variant is a ligand-independent transactivator modulating corticosteroid action. Mol Endocrinol. 2001;15:1586–98.PubMedCrossRefGoogle Scholar
  15. 15.
    Mihailidou AS, Le Loan TY, Mardini M, Funder JW. Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction. Hypertension. 2009;54:1306–12.PubMedCrossRefGoogle Scholar
  16. 16.
    Wang H, Shimosawa T, Matsui H, Kaneko T, Ogura S, Uetake Y, et al. Paradoxical mineralocorticoid receptor activation and left ventricular diastolic dysfunction under high oxidative stress conditions. J Hypertens. 2008;26:1453–62.PubMedCrossRefGoogle Scholar
  17. 17.
    • Shibata S, Nagase M, Yoshida S, Kawarazaki W, Kurihara H, Tanaka H, et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med. 2008;14:1370–6. This is the original paper that reported rac1 activate MR independent from aldosterone in the kidney, and this aldosterone-independent MR activation causes renal dysfunction.PubMedCrossRefGoogle Scholar
  18. 18.
    • Shibata S, Mu S, Kawarazaki H, Muraoka K, Ishizawa K, Yoshida S, et al. Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway. J Clin Invest. 2011;121:3233–43. This paper reported that rac1-mediated MR activation causes salt-sensitive hypertension in several rodent model.PubMedCrossRefGoogle Scholar
  19. 19.
    Rapp JP, Garrett MR, Deng AY. Construction of a double congenic strain to prove an epistatic interaction on blood pressure between rat chromosomes 2 and 10. J Clin Invest. 1998;101:1591–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Garrett MR, Zhang X, Dukhanina OI, Deng AY, Rapp JP. Two linked blood pressure quantitative trait loci on chromosome 10 defined by dahl rat congenic strains. Hypertension. 2001;38:779–85.PubMedCrossRefGoogle Scholar
  21. 21.
    Simon AR, Vikis HG, Stewart S, Fanburg BL, Cochran BH, Guan KL. Regulation of STAT3 by direct binding to the Rac1 GTPase. Science. 2000;290:144–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Ono A, Kuwaki T, Kumada M, Fujita T. Differential central modulation of the baroreflex by salt loading in normotensive and spontaneously hypertensive rats. Hypertension. 1997;29:808–14.PubMedCrossRefGoogle Scholar
  23. 23.
    Fujita T, Sato Y. Role of hypothalamic-renal noradrenergic systems in hypotensive action of potassium. Hypertension. 1992;20:466–72.PubMedCrossRefGoogle Scholar
  24. 24.
    Leenen FH, Ruzicka M, Huang BS. The brain and salt-sensitive hypertension. Curr Hypertens Rep. 2002;4:129–35.PubMedCrossRefGoogle Scholar
  25. 25.
    Feng D, Yang C, Geurts AM, Kurth T, Liang M, Lazar J, et al. Increased expression of NAD(P)H oxidase subunit p67(phox) in the renal medulla contributes to excess oxidative stress and salt-sensitive hypertension. Cell Metab. 2012;15:201–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Kishi T, Hirooka Y, Kimura Y, Ito K, Shimokawa H, Takeshita A. Increased reactive oxygen species in rostral ventrolateral medulla contribute to neural mechanisms of hypertension in stroke-prone spontaneously hypertensive rats. Circulation. 2004;109:2357–62.PubMedCrossRefGoogle Scholar
  27. 27.
    Fujita M, Ando K, Kawarazaki H, Kawarasaki C, Muraoka K, Ohtsu H, et al. Sympathoexcitation by brain oxidative stress mediates arterial pressure elevation in salt-induced chronic kidney disease. Hypertension. 2012;59:105–12.PubMedCrossRefGoogle Scholar
  28. 28.
    Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275–81.PubMedCrossRefGoogle Scholar
  30. 30.
    Lohmeier TE, Tillman LJ, Carroll RG, Brown AJ, Guyton AC. Malignant hypertensive crisis induced by chronic intrarenal norepinephrine infusion. Hypertension. 1984;6:I177–82.PubMedCrossRefGoogle Scholar
  31. 31.
    Guild SJ, Eppel GA, Malpas SC, Rajapakse NW, Stewart A, Evans RG. Regional responsiveness of renal perfusion to activation of the renal nerves. Am J Physiol Regul Integr Comp Physiol. 2002;283:R1177–86.PubMedGoogle Scholar
  32. 32.
    DiBona GF. Neural control of the kidney:past, present and future. Hypertension. 2003;41:621–4.PubMedCrossRefGoogle Scholar
  33. 33.
    • Gurley SB, Riquier-Brison AD, Schnermann J, Sparks MA, Allen AM, Haase VH, et al. AT1A angiotensin receptors in the renal proximal tubule regulate blood pressure. Cell Metab. 2011;13:469–75. It has been postulated that renal rather than cardiac or vascular AT1 receptor plays an important role in hypertension by these authors. In this paper, they precisely investigated the AT1 receptor at proximal tubule increases sodium resorption to induce volume-dependent hypertension.PubMedCrossRefGoogle Scholar
  34. 34.
    • Kahle KT, Ring AM, Lifton RP. Molecular physiology of the WNK kinases. Annu Rev Physiol. 2008;70:329–55. This is a comprehensive review of WNK kinase.PubMedCrossRefGoogle Scholar
  35. 35.
    Wilson FH, Disse-Nicodeme S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, et al. Human hypertension caused by mutations in WNK kinases. Science. 2001;293:1107–12.PubMedCrossRefGoogle Scholar
  36. 36.
    Lalioti MD, Zhang J, Volkman HM, Kahle KT, Hoffmann KE, Toka HR, et al. Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule. Nat Genet. 2006;38:1124–32.PubMedCrossRefGoogle Scholar
  37. 37.
    O'Reilly M, Marshall E, Macgillivray T, Mittal M, Xue W, Kenyon CJ, et al. Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo. J Am Soc Nephrol. 2006;17:2402–13.PubMedCrossRefGoogle Scholar
  38. 38.
    Li J, Wang DH. Function and regulation of epithelial sodium transporters in the kidney of a salt-sensitive hypertensive rat model. J Hypertens. 2007;25:1065–72.PubMedCrossRefGoogle Scholar
  39. 39.
    • Mu S, Shimosawa T, Ogura S, Wang H, Uetake Y, Kawakami-Mori F, et al. Epigenetic modulation of the renal beta-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nat Med. 2011;17(5):573–80. This paper showed that beta2 receptor-mediated HDAC8 inhibition leads to suppression of WNK4 and stimulates NCC to cause salt-sensitive hypertension.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Tatsuo Shimosawa
    • 1
    Email author
  • Shengyu Mu
    • 2
  • Shigeru Shibata
    • 3
  • Toshiro Fujita
    • 2
  1. 1.Faculty of Medicine, Department of Clinical LaboratoryUniversity of TokyoTokyoJapan
  2. 2.Research Center for Advanced Science and Technology, Division of Clinical EpigeneticsUniversity of TokyoTokyoJapan
  3. 3.Faculty of Medicine, Department of Endocrinology and NephrologyUniversity of TokyoTokyoJapan

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