Pathophysiology of salt sensitivity hypertension
Open accessAbstract
Dietary salt intake is the most important factor contributing to hypertension, but the salt susceptibility of blood pressure (BP) is different in individual subjects. Although the pathogenesis of salt-sensitive hypertension is heterogeneous, it is mainly attributable to an impaired renal capacity to excrete sodium (Na(+) ). We recently identified two novel mechanisms that impair renal Na(+) -excreting function and result in an increase in BP. First, mineralocorticoid receptor (MR) activation in the kidney, which facilitates distal Na(+) reabsorption through epithelial Na(+) channel activation, causes salt-sensitive hypertension. This mechanism exists not only in models of high-aldosterone hypertension as seen in conditions of obesity or metabolic syndrome, but also in normal- or low-aldosterone type of salt-sensitive hypertension. In the latter, Rac1 activation by salt excess causes MR stimulation. Second, renospecific sympathoactivation may cause an increase in BP under conditions of salt excess. Renal beta2 adrenoceptor stimulation in the kidney leads to decreased transcription of the gene encoding WNK4, a negative regulator of Na(+) reabsorption through Na(+) -Cl (-) cotransporter in the distal convoluted tubules, resulting in salt-dependent hypertension. Abnormalities identified in these two pathways of Na(+) reabsorption in the distal nephron may present therapeutic targets for the treatment of salt-sensitive hypertension.
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Cites
Takai, Y., Sasaki, T., & Matozaki, T. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.1.153 · Cited by 2,481 · see citing works
Krum, H., Schlaich, M., Whitbourn, R., Sobotka, P. A., Sadowski, J., Bartus, K., Kapelak, B., Walton, A., Sievert, H., Thambar, S., et al. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60566-3 · Cited by 2,108 · see citing works
Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney
Crowley, S. D., Gurley, S. B., Herrera, M., Ruiz, P., Griffiths, R., Kumar, A. P., Kim, H., Smithies, O., Le, T. H., & Coffman, T. M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0605545103 · Cited by 706 · see citing works
Weight Loss and the Renin-Angiotensin-Aldosterone System
Engeli, S., Böhnke, J., Gorzelniak, K., Janke, J., Schling, P., Bäder, M., Luft, F. C., & Sharma, A. M. (2005) · Hypertension · doi:10.1161/01.hyp.0000154361.47683.d3 · Cited by 625 · see citing works
The Effect of Weight Loss on the Sensitivity of Blood Pressure to Sodium in Obese Adolescents
Rocchini, A. P., Key, J., Bondie, D., Chico, R., Moorehead, C., Katch, V., & Martin, M. (1989) · New England Journal of Medicine · doi:10.1056/nejm198908313210905 · Cited by 621 · see citing works
Serum Aldosterone and the Incidence of Hypertension in Nonhypertensive Persons
Vasan, R. S., Evans, J. C., Larson, M. G., Wilson, P. W. F., Meigs, J. B., Rifai, N., Benjamin, E. J., & Levy, D. A. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa033263 · Cited by 573 · see citing works
Rac1 Activation Controls Nuclear Localization of β-catenin during Canonical Wnt Signaling
Wu, X., Tu, X., Joeng, K. S., Hilton, M. J., Williams, D. A., & Long, F. (2008) · Cell · doi:10.1016/j.cell.2008.01.052 · Cited by 481 · see citing works
Shibata, S., Nagase, M., Yoshida, S., Kawarazaki, W., Kurihara, H., Tanaka, H., Miyoshi, J., Takai, Y., & Fujita, T. (2008) · Nature Medicine · doi:10.1038/nm.1879 · Cited by 463 · see citing works
Self-citationBrod, J., Fencl, V., Hejl, Z., & Jirka, J. (1959) · PubMed · Cited by 420 · see citing works
A family of Acrp30/adiponectin structural and functional paralogs
Wong, G. W., Wang, J., Hug, C., Tsao, T., & Lodish, H. F. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403760101 · Cited by 419 · see citing works
WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion
Kahle, K. T., Wilson, F. H., Leng, Q., Lalioti, M. D., O'Connell, A. D., Dong, K., Rapson, A. K., MacGregor, G. G., Giebisch, G., Hébert, S., et al. (2003) · Nature Genetics · doi:10.1038/ng1271 · Cited by 374 · see citing works
Factors influencing blood pressure in salt-sensitive patients with hypertension
Fujita, T., Henry, W. L., Bartter, F. C., Lake, C. R., & Delea, C. S. (1980) · The American Journal of Medicine · doi:10.1016/0002-9343(80)90002-9 · Cited by 369 · see citing works
Self-citationLalioti, M. D., Zhang, J., Volkman, H. M., Kahle, K. T., Hoffmann, K. E., Toka, H. R., Nelson-Williams, C. J., Ellison, D. H., Flavell, R. A., Booth, C. J., et al. (2006) · Nature Genetics · doi:10.1038/ng1877 · Cited by 366 · see citing works
Long-term Effects of Neonatal Sodium Restriction on Blood Pressure
Geleijnse, J. M., Albert Hofman, D., Witteman, J. C. M., Hazebroek-Kampschreur, A. A. J. M., Valkenburg, H. A., & Grobbee, D. E. (1997) · Hypertension · doi:10.1161/01.hyp.29.4.913 · Cited by 319 · see citing works
Dahl, L. M., Heine, M., & Thompson, K. H. (1977) · Circulation Research · doi:10.1161/01.res.40.4.94 · Cited by 269 · see citing works
AT 1A Angiotensin Receptors in the Renal Proximal Tubule Regulate Blood Pressure
Gurley, S. B., Riquier‐Brison, A., Schnermann, J. B., Sparks, M. A., Allen, A. M., Haase, V. H., Snouwaert, J. N., Le, T. H., McDonough, A. A., Koller, B. H., et al. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.03.001 · Cited by 252 · see citing works
Enhanced Aldosterone Signaling in the Early Nephropathy of Rats with Metabolic Syndrome
Nagase, M., Yoshida, S., Shibata, S., Nagase, T., Gotoda, T., Ando, K., & Fujita, T. (2006) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006080944 · Cited by 247 · see citing works
Self-citationShibata, S., Mu, S., Kawarazaki, H., Muraoka, K., Ishizawa, K., Yoshida, S., Kawarazaki, W., Takeuchi, M., Ayuzawa, N., Miyoshi, J., et al. (2011) · Journal of Clinical Investigation · doi:10.1172/jci43124 · Cited by 238 · see citing works
Self-citationEpigenetic modulation of the renal β-adrenergic–WNK4 pathway in salt-sensitive hypertension
Mu, S., Shimosawa, T., Ogura, S., Wang, H., Uetake, Y., Kawakami-Mori, F., Marumo, T., Yatomi, Y., Geller, D. S., Tanaka, H., et al. (2011) · Nature Medicine · doi:10.1038/nm.2337 · Cited by 236 · see citing works
Self-citationBody Mass Index Predicts Aldosterone Production in Normotensive Adults on a High-Salt Diet
Bentley–Lewis, R., Adler, G. K., Perlstein, T. S., Seely, E. W., Hopkins, P. N., Williams, G. H., & Garg, R. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-1088 · Cited by 213 · see citing works
Epoxy-Keto Derivative of Linoleic Acid Stimulates Aldosterone Secretion
Goodfriend, T. L., Ball, D. L., Egan, B. M., Campbell, W. B., & Nithipatikom, K. (2004) · Hypertension · doi:10.1161/01.hyp.0000113294.06704.64 · Cited by 205 · see citing works
Angiotensin II and long-term arterial pressure regulation: the overriding dominance of the kidney.
Hall, J. E., BRANDS, M., & Henegar, J. R. (1999) · PubMed · Cited by 185 · see citing works
Kidneys and fluids in pressure regulation. Small volume but large pressure changes.
Guyton, A. C. (1992) · Hypertension · doi:10.1161/01.hyp.19.1_suppl.i2 · Cited by 164 · see citing works
Nagase, M., Matsui, H., Shibata, S., Gotoda, T., & Fujita, T. (2007) · Hypertension · doi:10.1161/hypertensionaha.107.091058 · Cited by 157 · see citing works
Self-citationRenal Sympathetic Nerve Responses to Tempol in Spontaneously Hypertensive Rats
Shokoji, T., Nishiyama, A., Fujisawa, Y., Hitomi, H., Kiyomoto, H., Takahashi, N., Kimura, S., Kohno, M., & Abe, Y. (2003) · Hypertension · doi:10.1161/01.hyp.0000049621.85474.cf · Cited by 147 · see citing works
The WNK Kinase Network Regulating Sodium, Potassium, and Blood Pressure
Hoorn, E. J., Nelson, J. H., McCormick, J. A., & Ellison, D. H. (2011) · Journal of the American Society of Nephrology · doi:10.1681/asn.2010080827 · Cited by 143 · see citing works
Heterogeneous responses to changes in dietary salt intake: the salt-sensitivity paradigm
Luft, F. C., & Weinberger, M. H. (1997) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/65.2.612s · Cited by 143 · see citing works
The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex
Yang, C., Zhu, X., & Ellison, D. H. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32033 · Cited by 134 · see citing works
Findings of the International Cooperative INTERSALT Study.
Stamler, J. F., Rose, G., Elliott, P., Dyer, A. R., Marmot, M. G., Kesteloot, H., & Stamler, R. (1991) · Hypertension · doi:10.1161/01.hyp.17.1_suppl.i9 · Cited by 129 · see citing works
WNK4 regulates activity of the epithelial Na + channel in vitro and in vivo
Ring, A. M., Cheng, S. X., Leng, Q., Kahle, K. T., Rinehart, J., Lalioti, M. D., Volkman, H. M., Wilson, F. H., Hébert, S., & Lifton, R. P. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611727104 · Cited by 127 · see citing works
Dietary Electrolyte–Driven Responses in the Renal WNK Kinase Pathway In Vivo
O’Reilly, M., Marshall, E., MacGillivray, T., Mittal, M., Wei, X., Kenyon, C. J., & Brown, R. W. (2006) · Journal of the American Society of Nephrology · doi:10.1681/asn.2005111197 · Cited by 123 · see citing works
Fujita, T., & Ando, K. (1984) · Hypertension · doi:10.1161/01.hyp.6.2.184 · Cited by 115 · see citing works
Self-citationProtective Effect of Dietary Potassium Against Vascular Injury in Salt-Sensitive Hypertension
Kido, M., Ando, K., Onozato, M. L., Tojo, A., Yoshikawa, M., Ogita, T., & Fujita, T. (2007) · Hypertension · doi:10.1161/hypertensionaha.107.098251 · Cited by 102 · see citing works
Self-citationThe Role of Aldosterone in the Metabolic Syndrome
Briet, M. B., & Schiffrin, E. L. (2011) · Current Hypertension Reports · doi:10.1007/s11906-011-0182-2 · Cited by 93 · see citing works
Xu, H., Fink, G. D., & Galligan, J. J. (2002) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00134.2002 · Cited by 91 · see citing works
Rho GTPases as Modulators of the Estrogen Receptor Transcriptional Response
Su, L. F., Knoblauch, R. E., & Garabedian, M. J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m005547200 · Cited by 90 · see citing works
Protective Effect of Potassium Against the Hypertensive Cardiac Dysfunction
Matsui, H., Shimosawa, T., Uetake, Y., Wang, H., Ogura, S., Kaneko, T., Liu, J., Ando, K., & Fujita, T. (2006) · Hypertension · doi:10.1161/01.hyp.0000232617.48372.cb · Cited by 89 · see citing works
Self-citationCharacterization of Brx, a novel Dbl family member that modulates estrogen receptor action
Rubino, D., Driggers, P. H., Arbit, D. I., et al. (1998) · Oncogene · doi:10.1038/sj.onc.1201783 · Cited by 79 · see citing works
Fiselier, T. J. W., Lijnen, P., Monnens, L. A. H., et al. (1983) · European Journal of Pediatrics · doi:10.1007/bf00445660 · Cited by 78 · see citing works
Salt Excess Causes Left Ventricular Diastolic Dysfunction in Rats With Metabolic Disorder
Matsui, H., Ando, K., Kawarazaki, H., Nagae, A., Fujita, M., Shimosawa, T., Nagase, M., & Fujita, T. (2008) · Hypertension · doi:10.1161/hypertensionaha.108.111815 · Cited by 75 · see citing works
Self-citationSodium susceptibility and potassium effects in young patients with borderline hypertension.
Fujita, T., Noda, H., & Ando, K. (1984) · Circulation · doi:10.1161/01.cir.69.3.468 · Cited by 73 · see citing works
Self-citationExperimental hypertension in young and adult animals.
Zicha, J., Kuneš, J., & Jelínek, J. (1986) · Hypertension · doi:10.1161/01.hyp.8.12.1096 · Cited by 64 · see citing works
Drumm, K., Kress, T. R., Gaßner, B., et al. (2006) · Cellular Physiology and Biochemistry · doi:10.1159/000091456 · Cited by 57 · see citing works
Biphasic Regulation of Na + -HCO 3 − Cotransporter by Angiotensin II Type 1A Receptor
Horita, S., Zheng, Y., Hara, C., et al. (2002) · Hypertension · doi:10.1161/01.hyp.0000036449.70110.de · Cited by 54 · see citing works
Systemic and regional hemodynamics in patients with salt-sensitive hypertension.
Fujita, T., Ando, K., & Ogata, E. (1990) · Hypertension · doi:10.1161/01.hyp.16.3.235 · Cited by 52 · see citing works
Self-citationRoles of ERK and cPLA2 in the Angiotensin II-Mediated Biphasic Regulation of Na+-HCO3 − Transport
Li, Y., Yamada, H., Kita, Y., et al. (2007) · Journal of the American Society of Nephrology · doi:10.1681/asn.2007030289 · Cited by 51 · see citing works
Ono, A., Kuwaki, T., Kumada, M., & Fujita, T. (1997) · Hypertension · doi:10.1161/01.hyp.29.3.808 · Cited by 48 · see citing works
Self-citationFujita, M., Kuwaki, T., Ando, K., et al. (2005) · Hypertension · doi:10.1161/01.hyp.0000165690.85505.37 · Cited by 46 · see citing works
Self-citationPinto, V., Pinho, M. J., Hopfer, U., José, P. A., & Soares-da-Silva, P. (2007) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-007-9680-6 · Cited by 44 · see citing works
Fujita, M., Ando, K., Kawarazaki, H., Kawarasaki, C., Muraoka, K., Ohtsu, H., Shimizu, H., & Fujita, T. (2011) · Hypertension · doi:10.1161/hypertensionaha.111.182923 · Cited by 42 · see citing works
Self-citationKawarazaki, H., Ando, K., Fujita, M., Matsui, H., Nagae, A., Muraoka, K., Kawarasaki, C., & Fujita, T. (2011) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00691.2010 · Cited by 41 · see citing works
Self-citationWilk, J. B., Djoussé, L., Arnett, D. K., et al. (2004) · American Journal of Hypertension · doi:10.1016/j.amjhyper.2004.06.003 · Cited by 34 · see citing works
Ando, K., & Fujita, M. (2011) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2011.05510.x · Cited by 28 · see citing works
Self-citationRole of hypothalamic-renal noradrenergic systems in hypotensive action of potassium.
Fujita, T., & Sato, Y. (1992) · Hypertension · doi:10.1161/01.hyp.20.4.466 · Cited by 26 · see citing works
Self-citationKawarazaki, H., Ando, K., Nagae, A., Fujita, M., Matsui, H., & Fujita, T. (2010) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfq197 · Cited by 26 · see citing works
Self-citationRenoprotective Effect of Pravastation in Salt-Loaded Dahl Salt-Sensitive Rats
Kido, M., Ando, K., Oba, S., & Fujita, T. (2005) · Hypertension Research · doi:10.1291/hypres.28.1009 · Cited by 24 · see citing works
Self-citationInduction of serum‐ and glucocorticoid‐induced kinase‐1 (SGK1) by cAMP regulates increases in α‐ENaC
Vasquez, M. M., Castro, R. J., SEIDNER, S. R., Henson, B. M., Ashton, D. J., & Mustafa, S. B. (2008) · Journal of Cellular Physiology · doi:10.1002/jcp.21534 · Cited by 24 · see citing works
Franceschini, N., MacCluer, J. W., Göring, H. H. H., et al. (2006) · Hypertension · doi:10.1161/01.hyp.0000231651.91523.7e · Cited by 22 · see citing works
Xu, G., Liu, A., & Liu, X. (2008) · Nephrology · doi:10.1111/j.1440-1797.2008.00998.x · Cited by 18 · see citing works
Li, J., & Wang, D. H. (2007) · Journal of Hypertension · doi:10.1097/hjh.0b013e3280a8b87d · Cited by 17 · see citing works
High calcium diet prevents baroreflex impairment in salt-loaded spontaneously hypertensive rats.
Ono, A., Kuwaki, T., Cao, W. H., et al. (1994) · Hypertension · doi:10.1161/01.hyp.24.1.83 · Cited by 12 · see citing works
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Research works printed but not linked: 2
- [11]11. Horita S, Zheng Y, Hara C, Yamada H, Kunimi M, Taniguchi S, 11. et al. Biphasic regulation of Na ϩ -HCO3 -cotransporter by angi- otensin II type 1A receptor. Hypertension. 2002;40:707 -12.
- [48]48. Ono A, Kuwaki T, Cao WH, Kumada M, Fujita T. High cal- 45. cium diet prevents barorefl ex impairment in salt-loaded spon- taneously hypertensive rats. Hypertension. 1994;24:83 -90.
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- Authors
- Ando, K., & Fujita, T.
- Affiliations
- The University of Tokyo (JP)
- Corresponding author
- Fujita, Toshiro
- ORCID
- Fujita, Toshiro
- Venue
- Annals of Medicine
- Publisher
- Informa UK Limited
- Published
- 2012-06
- Volume
- 44
- Issue
- sup1
- Pages
- S119-S126
- ISSN
- 0785-3890 (ISSN-L)
- 1365-2060
- OpenAlex
- W1983090164
- Semantic Scholar
- cdfa0b36595b213ff0785fe0667eb0aaa77efbbf
- Cited by
- 61
- References
- 61
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 11 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 5 · 2019: 3 · 2018: 5 · 2017: 4 · 2016: 4 · 2015: 4 · 2014: 2 · 2013: 8 · 2012: 1
- FWCI
- 0.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Annals of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (22590908, 24659410, 21229012)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Nursing › Nutrition and Dietetics › Sodium Intake and Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- salt-sensitive hypertension, salt intake, renal sodium excretion, mineralocorticoid receptor, epithelial sodium channel, aldosterone, Rac1, beta2-adrenergic receptor, WNK4, NaCl cotransporter, distal convoluted tubule, blood pressure regulation, metabolic syndrome, obesity
- MeSH terms
- Aldosterone, Blood Pressure, Humans, Hypertension, Kidney, Sodium, Signal Transduction, Protein Serine-Threonine Kinases, Sodium Chloride, Dietary, Receptors, Mineralocorticoid, rac1 GTP-Binding Protein
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