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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThis article discusses the mechanisms of salt-sensitive hypertension. The link between salt intake and hypertension is not a recent discovery but, rather, has been known for a half-century on the basis of studies conducted worldwide. Subjects with hypertension can be classified as salt-insensitive and salt-sensitive. It is beginning to be understood that salt sensitivity can be modulated by multiple mechanisms, including the renal sympathetic nervous system, the mineralocorticoid receptor, and aldosterone.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EHypertensive Disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ECardiology \u0026amp; Cardiovascular Medicine\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EHypertensive Disease\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EToshiro Fujita, MD, University of Tokyo, Tokyo, Japan, discussed the mechanisms of salt-sensitive hypertension. The link between salt intake and hypertension is not a recent discovery but, rather, has been known for a half-century on the basis of studies conducted worldwide. Subjects with hypertension can be classified as salt-insensitive and salt-sensitive. The former group exhibits a stable blood pressure (BP) with different levels of salt intake (as measured by the urinary excretion of sodium). Subjects with salt-sensitive hypertension display increasing BP with increased salt intake. It is beginning to be understood that salt sensitivity can be modulated by multiple mechanisms, including the renal sympathetic nervous system, the mineralocorticoid receptor, and aldosterone.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EExcessive salt intake in the context of elevated aldosterone leads to the activation of the mineralocorticoid receptor and aldosterone-sensitive epithelial sodium channels in distal nephrons. The result is increased sodium reabsorption, which drives hypertension [Shibata S et al. \u003Cem\u003EHypertension\u003C\/em\u003E 2007] and proteinuria [Nagase M et al. \u003Cem\u003EJ Am Soc Nephrol\u003C\/em\u003E 2006]. This phenomenon was illustrated in experiments conducted in Sprague-Dawley rats fed a low-salt or high-salt diet in the background of a continuous infusion of aldosterone. BP increased linearly with the time of treatment only for those with a high-salt diet, whereas control rats and those fed the low-salt diet with aldosterone infusion displayed a similar pattern of near-constant and significantly lower BP [Shibata S et al. \u003Cem\u003EHypertension\u003C\/em\u003E 2007]. The rats fed the high-fat diet and treated with aldosterone also displayed markedly higher levels of urinary protein. Another study demonstrated proteinuria in obese rats in the presence of excess aldosterone, which was normalized after treatment with a mineralocorticoid receptor blocker [Nagase M et al. \u003Cem\u003EJ Am Soc Nephrol\u003C\/em\u003E 2006].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EIt appears that activation of the mineralocorticoid receptor may promote hypertension, chronic kidney disease [Nagase M et al. \u003Cem\u003EHypertension\u003C\/em\u003E 2007], and cardiovascular disease [Matsui H et al. \u003Cem\u003EHypertension\u003C\/em\u003E 2008] not only in an aldosterone-dependent fashion, as discussed above, but also independent of aldosterone. The observation that plasma aldosterone concentration is not always elevated in obese subjects and that treatment with an aldosterone blocker decreases proteinuria in obese hypertensive subjects suggests that activation of the mineralocorticoid receptor can also occur independent of aldosterone. The identity of the other aldosterone activator(s) remains unclear. Known activators of steroid receptors include, however, SRC-1, Ras, mitogen-activated protein kinase, Smad3, protein kinase A, and Ubc9.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EAnother potential candidate protein is Rac1, a small G protein that is involved in regulation of the actin cytoskeleton, cell migration, and the response to oxidative stress. It is thought that Rac1 may function in concert with aldosterone in the activation of the mineralocorticoid receptor, which preludes salt-sensitive hypertension and renal damage [Shibata S et al. \u003Cem\u003ENature Medicine\u003C\/em\u003E 2008]. Experiments in salt-sensitive rat strains (Dahl-S) implicated Rac1 involvement at the level of the kidney in mineralocorticoid receptor\u2014dependent hypertension [Shibata S. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E 2011]. Cross-transplant experiments involving renal homografts highlighted the importance of the kidneys in the process of hypertension-related damage in Dahl-S rats [Dahl LK, Heien M. \u003Cem\u003ECirc Res\u003C\/em\u003E 1975].\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EA model to explain these observations is summarized in \u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E. In the model, downregulation of aldosterone production occurs with excessive salt intake. In salt-resistant organisms, Rac1 and mineralocorticoid receptor are downregulated, resulting in normotension. In salt-sensitive organisms, Rac1 and the mineralocorticoid receptor are upregulated, leading to BP elevation [Shibata S et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E 2011; Shibata S et al. \u003Cem\u003ENature Medicine\u003C\/em\u003E 2008].\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/4\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Renal Rac1 and Salt Sensitivity\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-342883062\u0022 data-figure-caption=\u0022Renal Rac1 and Salt Sensitivity\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/4\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/4\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/4\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14641\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-7\u0022 class=\u0022first-child\u0022\u003ERenal Rac1 and Salt Sensitivity\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EAldo=aldosterone; BP=blood pressure; MR=mineralocorticoid receptor; SS-HT=salt-sensitive hypertensive.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003EReproduced with permission from T Fujita, MD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-8\u0022\u003EIn addition to aldosterone and the mineralocorticoid receptor, the renal sympathetic nervous system has been implicated in salt sensitivity. Salt loading increases renal sympathetic nervous system activity in salt-sensitive hypertensive rats compared with normotensive rats. In one study, salt-insensitive rats displayed a similar pattern of renal turnover of norepinephrine whether they consumed a low-salt or high-salt diet, whereas salt-sensitive rats had a significantly (p\u0026lt;0.01) more pronounced decline in norepinephrine turnover when consuming a high-salt diet [Fujita T, Sato Y. \u003Cem\u003EHypertension\u003C\/em\u003E 1992]. In other experiments, the infusion of norepinephrine induced salt-sensitive hypertension in mice, which was associated with the downregulation of renal WNK4 and upregulation of the sodium chloride (NaCl) cotransporter.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EThe root of this effect may be the increased action of brain reactive oxygen species in the presence of elevated levels of salt (and in obese individuals) [Nagae A et al. \u003Cem\u003ECirculation\u003C\/em\u003E 2009]. Renal sympathetic nervous system overactivity may downregulate the WNK4 protein, which in turn activates the NaCl cotransporter located in the distal convoluted tubules. This activation leads to retention of sodium and, consequently, hypertension [Mu S et al. \u003Cem\u003ENature Medicine\u003C\/em\u003E 2011].\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EThe glucocorticoid receptor has also been implicated in salt-sensitive hypertension in mice. Normal mice continuously exposed to isoproterenol, a beta adrenergic agonist, developed hypertension when dietary salt levels were elevated. In contrast, glucocorticoid receptor knockout mice displayed no change in mean arterial pressure in the continuous presence of isoproterenol and in high dietary salt concentrations.\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EGiven the complexity of the mechanisms identified to date for salt-sensitive hypertension, it is likely that other, unidentified factors contribute to this phenomenon in humans (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/4\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Complexity of Salt-Sensitive Hypertension in Humans\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-342883062\u0022 data-figure-caption=\u0022Complexity of Salt-Sensitive Hypertension in Humans\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/4\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/4\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/18\/4\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14642\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-12\u0022 class=\u0022first-child\u0022\u003EComplexity of Salt-Sensitive Hypertension in Humans\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-3\u0022\u003ENSS HT=non-salt-sensitive hypertensive; SS HT=salt-sensitive hypertensive; MR=mineralocorticoid receptor\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-4\u0022\u003EReproduced with permission from T Fujita, MD.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-5\u0022\u003E*On November 21, 2014, this was changed from Racl-MR to Rac1-MR. **On November 21, 2014, this was changed from SNS-WNK-NCC to SNS-WNK4-NCC.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-13\u0022\u003EFrom an evolutionary perspective, aldosterone may have promoted survival as organisms moved from the sea to the relatively low-salt terrestrial environment by driving sodium homeostasis. As human salt intake began to increase thousands of years ago, plasma aldosterone became suppressed by inhibition of the renin\u2014angiotensin system, which resulted in normal BP. It appears, however, that the modern-day prevalence of high-salt diets and obesity may have exaggerated the role of the Rac1\u2013mineralocorticoid receptor and SNS\u2014WNK4\u2013NCC pathways in BP control, leading to an increasing prevalence of salt-sensitive hypertension. Salt-sensitive hypertension, chronic kidney disease, and cardiovascular disease are examples of what Dr. Fujita termed \u201cdiseases of civilization.\u201d\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/18\/4.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzp0w9\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzp0w9\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}