Novel mechanisms of salt-sensitive hypertension

Abstract

A high dietary sodium-consumption level is considered the most important lifestyle factor that can be modified to help prevent an increase in blood pressure and the development of hypertension. Despite numerous studies over the past decades, the pathophysiology explaining why some people show a salt-sensitive blood pressure response and others do not is incompletely understood. Here, a brief overview of the latest mechanistic insights is provided, focusing on the mononuclear phagocytic system and inflammation, the gut–kidney axis, and epigenetics. The article also discusses the effects of 3 types of novel drugs on salt-sensitive hypertension—sodium–glucose cotransporter 2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, and aldosterone synthase inhibitors. The conclusion is that besides kidney-centered mechanisms, vasoconstrictor mechanisms are also relevant for both the understanding and treatment of this blood pressure phenotype. A high dietary sodium-consumption level is considered the most important lifestyle factor that can be modified to help prevent an increase in blood pressure and the development of hypertension. Despite numerous studies over the past decades, the pathophysiology explaining why some people show a salt-sensitive blood pressure response and others do not is incompletely understood. Here, a brief overview of the latest mechanistic insights is provided, focusing on the mononuclear phagocytic system and inflammation, the gut–kidney axis, and epigenetics. The article also discusses the effects of 3 types of novel drugs on salt-sensitive hypertension—sodium–glucose cotransporter 2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, and aldosterone synthase inhibitors. The conclusion is that besides kidney-centered mechanisms, vasoconstrictor mechanisms are also relevant for both the understanding and treatment of this blood pressure phenotype. A high dietary sodium-consumption level is considered the most important lifestyle factor that can be modified to help prevent an increase in blood pressure (BP) and the development of hypertension.1World Health OrganizationGuideline: Sodium Intake for Adults and Children. World Health Organisation, 2012Google Scholar These BP effects relate specifically to sodium chloride (salt), but not necessarily to other sodium-containing salts.2Beynon-Cobb B. Louca P. Hoorn E.J. et al.Effect of sodium bicarbonate on systolic blood pressure in CKD: a systematic review and meta-analysis.Clin J Am Soc Nephrol. 2023; 18: 435-445Crossref PubMed Scopus (2) Google Scholar Guidelines of the World Health Organization recommend limiting sodium consumption to <2 g/d (i.e., salt < 5 g/d) in order to improve BP control and associated cardiovascular outcomes in the general population.1World Health OrganizationGuideline: Sodium Intake for Adults and Children. World Health Organisation, 2012Google Scholar Intriguingly, dietary sodium restriction does not improve BP control in everyone, and sometimes it even increases BP.3Obarzanek E. Proschan M.A. Vollmer W.M. et al.Individual blood pressure responses to changes in salt intake: results from the DASH-Sodium trial.Hypertension. 2003; 42: 459-467Crossref PubMed Scopus (161) Google Scholar The change in BP following sodium loading also shows great variability, and this response can be used to discriminate salt-sensitive (SS) individuals from salt-resistant individuals in whom BP does not increase after the sodium load (Figure 1).4Johnson R.J. Herrera-Acosta J. Schreiner G.F. et al.Subtle acquired renal injury as a mechanism of salt-sensitive hypertension.N Engl J Med. 2002; 346: 913-923Crossref PubMed Scopus (391) Google Scholar Several factors that increase salt-sensitivity have been identified, including aging, female sex, unhealthy lifestyle (e.g., overweight and a potassium-poor diet), a history of low birth weight or small gestational age, African descent, low-renin status, sympathetic hyperactivity, epithelial sodium-channel variants, and comorbidities such as hypertension, insulin-resistance, or chronic kidney disease (CKD).4Johnson R.J. Herrera-Acosta J. Schreiner G.F. et al.Subtle acquired renal injury as a mechanism of salt-sensitive hypertension.N Engl J Med. 2002; 346: 913-923Crossref PubMed Scopus (391) Google Scholar,5Mutchler S.M. Kirabo A. Kleyman T.R. Epithelial sodium channel and salt-sensitive hypertension.Hypertension. 2021; 77: 759-767Crossref PubMed Scopus (41) Google Scholar The clinical significance of the SS BP phenotype is emphasized by its link with increased cardiovascular risk and mortality, and with intermediate kidney outcomes, such as proteinuria.6Bihorac A. Tezcan H. Ozener C. et al.Association between salt sensitivity and target organ damage in essential hypertension.Am J Hypertens. 2000; 13: 864-872Crossref PubMed Scopus (68) Google Scholar,7Weinberger M.H. Fineberg N.S. Fineberg S.E. et al.Salt sensitivity, pulse pressure, and death in normal and hypertensive humans.Hypertension. 2001; 37: 429-432Crossref PubMed Google Scholar Nevertheless, despite numerous studies over the past 50 years, the pathophysiology explaining why some show an SS BP response, and others show a salt-resistant BP response, is incompletely understood. Here, a brief overview of the latest mechanistic insights and therapeutic options is provided.Editor’s NoteSalt-sensitive hypertension is a long-known subcategory of arterial hypertension. The effect of dietary salt intake on blood pressure in the general population remains a hot topic. The authors of this review address novel, recently identified mechanisms that explain why some people are sensitive to high-salt diets, whereas others are not, including the role of inflammation, an implication of the gut–kidney axis, and several epigenetic modifications. The review ends with a discussion of the effects of new drugs on salt-sensitive hypertension, paving the way to new treatment possibilities. Salt-sensitive hypertension is a long-known subcategory of arterial hypertension. The effect of dietary salt intake on blood pressure in the general population remains a hot topic. The authors of this review address novel, recently identified mechanisms that explain why some people are sensitive to high-salt diets, whereas others are not, including the role of inflammation, an implication of the gut–kidney axis, and several epigenetic modifications. The review ends with a discussion of the effects of new drugs on salt-sensitive hypertension, paving the way to new treatment possibilities. According to traditional concepts, sodium homeostasis is responsible for a stable milieu intérieur and is a key factor for BP control.8Kurtz T.W. Pravenec M. DiCarlo S.E. Mechanism-based strategies to prevent salt sensitivity and salt-induced hypertension.Clin Sci (Lond). 2022; 136: 599-620Crossref PubMed Scopus (5) Google Scholar In SS individuals, a high level of sodium consumption is expected to lead to sodium accumulation and concurrent extracellular fluid volume expansion, at the cost of a BP increment (Figure 1).8Kurtz T.W. Pravenec M. DiCarlo S.E. Mechanism-based strategies to prevent salt sensitivity and salt-induced hypertension.Clin Sci (Lond). 2022; 136: 599-620Crossref PubMed Scopus (5) Google Scholar Meticulously performed sodium-balance studies in humans, however, have shown that the association between sodium and BP is more complex.9Wenstedt E.F.E. Olde Engberink R.H.G. Vogt L. Sodium handling by the blood vessel wall: critical for hypertension development.Hypertension. 2018; 71: 990-996Crossref PubMed Scopus (18) Google Scholar The prevailing 2-compartment view on sodium homeostasis, in which body water is divided over the intra- and extracellular fluid space, has been revised due to the reappraisal of a third compartment, the interstitium, in which sodium can accumulate without concurrent water retention.9Wenstedt E.F.E. Olde Engberink R.H.G. Vogt L. Sodium handling by the blood vessel wall: critical for hypertension development.Hypertension. 2018; 71: 990-996Crossref PubMed Scopus (18) Google Scholar Subsequent studies have shown that tissue sodium accumulation—in the skin, muscles, and endothelial glycocalyx—relates to SS conditions, including diabetes, hypertension, and CKD.9Wenstedt E.F.E. Olde Engberink R.H.G. Vogt L. Sodium handling by the blood vessel wall: critical for hypertension development.Hypertension. 2018; 71: 990-996Crossref PubMed Scopus (18) Google Scholar Increased tissue sodium accumulation, facilitated by negatively charged polymeric disaccharides called glycosaminoglycans, was associated with impaired vasodilatation in response to high levels of sodium, much in keeping with experimental observations showing that salt sensitivity is caused merely by sodium-induced increases in vascular resistance rather than expansion of extracellular fluid volume and cardiac output.8Kurtz T.W. Pravenec M. DiCarlo S.E. Mechanism-based strategies to prevent salt sensitivity and salt-induced hypertension.Clin Sci (Lond). 2022; 136: 599-620Crossref PubMed Scopus (5) Google Scholar,9Wenstedt E.F.E. Olde Engberink R.H.G. Vogt L. Sodium handling by the blood vessel wall: critical for hypertension development.Hypertension. 2018; 71: 990-996Crossref PubMed Scopus (18) Google Scholar Besides tissue sodium accumulation, the autonomic nervous system plays a pivotal role in decreased arteriolar vasodilatory capacity upon sodium loading.10Castiglioni P. Parati G. Lazzeroni D. et al.Hemodynamic and autonomic response to different salt intakes in normotensive individuals.J Am Heart Assoc. 2016; 5e003736Crossref PubMed Scopus (15) Google Scholar Yet, in patients with diabetes, the BP increase after a 7-day high-salt diet was not associated with systemic vascular resistance or extracellular fluid volume expansion.11Wenstedt E.F.E. Rorije N.M.G. Olde Engberink R.H.G. et al.Effect of high-salt diet on blood pressure and body fluid composition in patients with type 1 diabetes: randomized controlled intervention trial.BMJ Open Diabetes Res Care. 2020; 8e001039Crossref PubMed Scopus (9) Google Scholar Rather, in these patients, a central role for skin macrophages and the dermal lymphatic system was apparent,12Wenstedt E.F.E. Olde Engberink R.H. Rorije N.M.G. et al.Salt-sensitive blood pressure rise in type 1 diabetes patients is accompanied by disturbed skin macrophage influx and lymphatic dilation—a proof-of-concept study.Transl Res. 2020; 217: 23-32Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar which is in line with previous rat experiments.13Machnik 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: 545-552Crossref PubMed Scopus (742) Google Scholar In these studies, tonicity-responsive enhancer-binding protein (also known as nuclear factor of activated T cells) mediated vascular endothelial growth factor–C signaling in macrophages in response to increased tissue sodium storage, and caused salt-induced hypertension.13Machnik 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: 545-552Crossref PubMed Scopus (742) Google Scholar An incapacity to expand the tissue lymph capillary network after excessive sodium intake (8% saline) was strongly associated with the sodium-induced BP response.13Machnik 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: 545-552Crossref PubMed Scopus (742) Google Scholar Subsequent studies revealed that sodium increases monocyte interleukin (IL)-6 production and C-C chemokine receptor type 2 receptor expression. This upregulates tissue monocyte infiltration and plasma monocyte chemoattractant protein-1 and explains the higher skin proinflammatory macrophage densities that are seen after a high-sodium diet.14Wenstedt E.F. Verberk S.G. Kroon J. et al.Salt increases monocyte CCR2 expression and inflammatory responses in humans.JCI Insight. 2019; 4e130508Crossref PubMed Scopus (26) Google Scholar In vitro, macrophages demonstrate a predominantly proinflammatory phenotype upon high-sodium exposure, characterized by secretion of IL-6 and tumor necrosis factor-α, although IL-10 secretion is enhanced as well.14Wenstedt E.F. Verberk S.G. Kroon J. et al.Salt increases monocyte CCR2 expression and inflammatory responses in humans.JCI Insight. 2019; 4e130508Crossref PubMed Scopus (26) Google Scholar Given the observations from animal studies that BP increments depend on monocyte and macrophage depletion,13Machnik 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: 545-552Crossref PubMed Scopus (742) Google Scholar and the observations in patients with diabetes that disturbed skin macrophage influx links lymphatic density to salt sensitivity,12Wenstedt E.F.E. Olde Engberink R.H. Rorije N.M.G. et al.Salt-sensitive blood pressure rise in type 1 diabetes patients is accompanied by disturbed skin macrophage influx and lymphatic dilation—a proof-of-concept study.Transl Res. 2020; 217: 23-32Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar the mononuclear phagocytic system–derived inflammatory response should be considered a new key player in salt The is the of of a is that it the and salt sensitivity (Figure both (i.e., and systemic and G. et and Nephrol. 2023; PubMed Scopus Google Scholar The for this from SS and salt-resistant which have B. et for a link between and hypertension in the PubMed Scopus Google Scholar are key to association from G. et and Nephrol. 2023; PubMed Scopus Google Scholar a from on a diet on an diet whereas the increased J. et blood pressure by the of in high salt-induced Res. 2020; PubMed Scopus Google Scholar that a from excessive an response to and higher plasma levels of proinflammatory to normal et dietary salt-induced Insight. 2019; Scholar sodium intake increased inflammation, as an accumulation of and in the of both and et dietary salt-induced Insight. 2019; Scholar A is that the production of proinflammatory and with sodium is by excessive sodium intake in in a higher of in the and S.M. et and PubMed Scopus Google Scholar with decreased BP and the of in and with a high salt S.M. et and PubMed Scopus Google Scholar These studies not S.M. et and PubMed Scopus Google Scholar or et dietary salt-induced Insight. 2019; Scholar changes in kidney or other the of a gut–kidney that and kidney is by the or treatment with by the the kidney with changes in inflammatory such as E. et diet and change the and prevent the development of hypertension and in hypertensive PubMed Scopus Google Scholar the systemic BP in hypertensive E. et diet and change the and prevent the development of hypertension and in hypertensive PubMed Scopus Google H. 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