Role of Rho in Salt-Sensitive Hypertension
Authors: Toshiro Fujita
Wakako Kawarazaki
Journal: International Journal of Molecular Sciences (2021)
Discipline: CHEMISTRY
Keywords: Rac; Rho; Wnt; aging; angiotensin II
Affiliations: Research Center for Advanced Science and Technology, Division of Clinical Epigenetics, The University of Tokyo, Meguro-ku, Tokyo 153-8904, Japan.

Abstract:  A high amount of salt in the diet increases blood pressure (BP) and leads to salt-sensitive hypertension in individuals with impaired renal sodium excretion. Small guanosine triphosphatase (GTP)ase Rho and Rac, activated by salt intake, play important roles in the pathogenesis of salt-sensitive hypertension as key switches of intracellular signaling. Focusing on Rho, high salt intake in the central nervous system increases sodium concentrations of cerebrospinal fluid in salt-sensitive subjects via Rho/Rho kinase and renin-angiotensin system activation and causes increased brain salt sensitivity and sympathetic nerve outflow in BP control centers. In vascular smooth muscle cells, Rho-guanine nucleotide exchange factors and Rho determine sensitivity to vasoconstrictors such as angiotensin II (Ang II), and facilitate vasoconstriction via G-protein and Wnt pathways, leading to increased vascular resistance, including in the renal arteries, in salt-sensitive subjects with high salt intake. In the vascular endothelium, Rho/Rho kinase inhibits nitric oxide (NO) production and function, and high salt amounts further augment Rho activity via asymmetric dimethylarginine, an endogenous inhibitor of NO synthetase, causing aberrant relaxation and increased vascular tone. Rho-associated mechanisms are deeply involved in the development of salt-sensitive hypertension, and their further elucidation can help in developing effective protection and new therapies. 

Retracted: No

PubPeer comments:
 I read with great interest the review article by Kawarazaki and Fujita which addresses the important role of Rho in salt sensitive hypertension [1]. The authors seem to endorse the historical theory of Guyton et al. by stating that u201csalt-sensitive individuals have impaired sodium excretion from the kidneys, which leads to salt retention in the body, increased circulating blood volume, increased cardiac output, and ultimately increased peripheral vascular resistance, resulting in increased BP.u201d This is surprising because it has been demonstrated that in response to increases in salt intake in humans, salt sensitive subjects do not have impaired sodium excretion compared to normal controls u2013 they do not excrete sodium more slowly or retain more sodium than salt resistant normal controls [2-6]. If there is no difference in sodium excretion in response to increased salt intake between salt sensitive subjects and salt resistant normals, what causes blood pressure to go up more in salt sensitive subjects than in salt resistant normal controls? It cannot be claimed that impaired sodium excretion and greater sodium retention accounts for the greater BP response to salt in salt sensitive subjects versus salt resistant normals. According to Beard, Guytonu2019s model of salt and blood pressure control has been disproven [7]. Guytonu2019s model is based on the assumption that in response to increases in salt intake, normal subjects excrete salt u201calmost as rapidly as it can be infused or drunku201d and retain little or no salt in response to salt loading [8]. This assumption of Guytonu2019s model has been invalidated [9]. Based on this invalidated assumption, Guytonu2019s theory of salt sensitivity incorrectly holds that in salt sensitive subjects, increased salt intake increases BP by causing greater retention of sodium in salt sensitive subjects than in normal subjects. In fact, studies in humans and in animals have shown that in response to increases in salt intake, normal salt resistant individuals retain large amounts of sodium - just as much as salt sensitive subjects - yet blood pressure increases only in salt sensitive subjects [2-6, 10-13]. It is being increasingly recognized that in response to increases in salt intake, subnormal decreases in vascular resistance including renal vascular resistance, not subnormal excretion of sodium (compared to salt loaded controls), together with normal increases in cardiac output, initiates salt-induced increases in blood pressure [5, 6, 14-16]. As nicely discussed by Kawararzaki and Fujita [1], Rho may be involved in salt sensitivity by mediating abnormal vascular resistance responses to salt. 1.tKawarazaki, W. and T. Fujita, Role of Rho in Salt-Sensitive Hypertension. Int J Mol Sci, 2021. 22(6). 2.tIshii, M., et al., Role of the aldosterone system in the salt-sensitivity of patients with benign essential hypertension. Jpn Heart J, 1983. 24: p. 79-89. 3.tWedler, B., et al., Sodium kinetics in salt-sensitive and salt-resistant normotensive and hypertensive subjects. J Hypertens, 1992. 10(7): p. 663-9. 4.tSchmidlin, O., A.F. Sebastian, and R.C. Morris, Jr., What initiates the pressor effect of salt in salt-sensitive humans? Observations in normotensive blacks. Hypertension, 2007. 49(5): p. 1032-9. 5.tSchmidlin, O., et al., Salt sensitivity in blacks: evidence that the initial pressor effect of NaCl involves inhibition of vasodilatation by asymmetrical dimethylarginine. 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Hypertension, 1989. 13(3): p. 243-9. 12.tHu, L. and R.D. Manning, Jr., Role of nitric oxide in regulation of long-term pressure-natriuresis relationship in Dahl rats. Am J Physiol, 1995. 268(6 Pt 2): p. H2375-83. 13.tKanagy, N.L. and G.D. Fink, Losartan prevents salt-induced hypertension in reduced renal mass rats. Journal of Pharmacology and Experimental Therapeutics, 1993. 265: p. 1131-1136. 14.tKurtz, T.W., et al., The pivotal role of renal vasodysfunction in salt sensitivity and the initiation of salt-induced hypertension. Curr Opin Nephrol Hypertens, 2018. 27(2): p. 83-92. 15.tWu, J., et al., Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension. Cardiovasc Res, 2021. 117(1): p. 308-319. 16.tRalph, A.F., et al., Activation of the Sympathetic Nervous System Promotes Blood Pressure Salt-Sensitivity in C57BL6 J Mice. Hypertension, 2021. 77(1): p. 158-168. , 
 Thank you for your comment on our review article entitled u201cRole of Rho in salt-sensitive hypertensionu201d (1). According to the potential role of renal dysfunction in salt-sensitive hypertension, Kawasaki et al. found that salt-sensitive hypertensive subjects retained more sodium than salt-resistant subjects during the high sodium intake (2). In contrast, Ishii et al. reported that salt-sensitive hypertensive subjects excreted sodium as rapidly as salt-resistant normotensive subjects (3), and it led to the conclusion that salt-sensitive hypertension is not attributed to renal dysfunction (4). Based upon Guytonu2019s hypothesis, however, the kidneys of hypertensive subjects are perfused at increased BP, and in turn, elevated BP induces natriuresis (5). Thus, the finding that urinary sodium excretion rates are similar between hypertensives and normotensives suggests that hypertensives have an impaired renal capacity to excrete sodium in the urine (6). In the presence of elevated BP, the impaired renal function for sodium excretion is cancelled in hypertensives. With the shifted pressure-natriuresis curve to higher BP, renal capacity of sodium excretion appears to be normal. We recently found that aged mice fed a high salt diet have augmented response of renal blood flow (RBF) reduction to the infusion of angiotensin II (Ang II) through activation of vascular Wnt-RhoA pathway, resulting in salt-induced BP elevation (7). Ang II-dependent hypertension is caused from reduced RBF and decreased urinary excretion of sodium, since Ang II-induced hypertension is diminished in mice lacking type 1A angiotensin receptor in smooth muscle cells, associated with preservation of RBF and inhibition of sodium retention (8). Moreover, a high salt intake increases RBF in salt-resistant humans but decreases in salt-sensitive hypertensive subjects (9). Taken together, these findings led us to the plausible hypothesis that an abnormal renal hemodynamic adaptation may be causal in the pathogenesis of salt-sensitive hypertension (9, 10). 1.tKawarazaki W et al. Int J Mol Sci 2021, 22, 2958. https: doi.org 10.3390 ijms22062958 2.tKawasaki T, et al. Am J Med 1978; 64:193-198 3.tIshii M et al. Jpn Heart J 1983; 24:79-89 4.tKurtz TW et al. Hypertension 2015; 65: 932-941 5.tMizelle Hl et al. Hypertension 1993; 22: 102-110 6.tHall J et al. Circulation 2016; 133: 894-907 7.tKawarazaki W et al. J Clin Invest 2020; 130; 4152-4166 8.tSparks MA, et al. J Am Soc Nephrol 2015;26:2953-2962 9.tCampese VM, et al. Hypertension 1991;18:805-812 10.tKurtz TW, et al. Curr Opin Nephrol Hypertens 2018;27:83-92 , 
 #2 Thank you for your reply. You mention that  the finding that urinary sodium excretion rates are similar between hypertensives and normotensives suggests that hypertensives have an impaired renal capacity to excrete sodium in the urine. If the urine sodium excretion rates are similar between salt sensitive subjects and normotensive control subjects in response to increases in salt intake, how do similar urine sodium excretion rates cause BP to increase more in salt sensitive subjects than in normotensive control subjects ? Similarly, given that salt resistant normal subjects retain large amounts of sodium - same as salt sensitive subjects - why doesn t salt retention increase BP in salt resistant subjects? If salt retention is the problem causing elevated BP, why doesn t salt retention increase BP in salt resistant subjects? ,