Novel mechanisms of salt-sensitive hypertension

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 sensitivity. The large intestine is the main site of absorption of sodium; thus, a plausible possibility is that it may impact the gut microbiome and salt sensitivity (Figure 2), via both localized (i.e., intestinal) and systemic immune-dependent and -independent mechanisms.15O'Donnell J.A. Zheng T. Meric G. et al.The gut microbiome and hypertension.Nat Rev Nephrol. 2023; 19: 153-167Crossref PubMed Scopus (21) Google Scholar The first evidence for this came from Dahl SS and salt-resistant rats, which have distinct microbiomes.16Mell B. Jala V.R. Mathew A.V. et al.Evidence for a link between gut microbiota and hypertension in the Dahl rat.Physiol Genomics. 2015; 47: 187-197Crossref PubMed Scopus (290) Google Scholar Studies using fecal microbiota transplantation are key to differentiating association from causation.15O'Donnell J.A. Zheng T. Meric G. et al.The gut microbiome and hypertension.Nat Rev Nephrol. 2023; 19: 153-167Crossref PubMed Scopus (21) Google Scholar Indeed, a fecal microbiota transplantation from Wistar rats on a normal-sodium diet (0.49%) into Wistar rats on an excessive-sodium diet (8%) normalized BP, whereas the reverse fecal microbiota transplantation increased BP.17Yan X. Jin J. Su X. et al.Intestinal flora modulates blood pressure by regulating the synthesis of intestinal-derived corticosterone in high salt-induced hypertension.Circ Res. 2020; 126: 839-853Crossref PubMed Scopus (102) Google Scholar Moreover, germ-free mice that received a fecal microbiota transplantation from excessive sodium–fed mice had an exaggerated response to angiotensin II and higher plasma levels of proinflammatory cytokines (IL-6, IL-17) relative to normal sodium–fed recipients.18Ferguson J.F. Aden L.A. Barbaro N.R. et al.High dietary salt-induced dendritic cell activation underlies microbial dysbiosis-associated hypertension.JCI Insight. 2019; 5e126241Google Scholar Excessive sodium intake increased intestinal inflammation, demonstrated as an accumulation of leukocytes, macrophages, and isolevuglandins in the colon, of both mice and humans.18Ferguson J.F. Aden L.A. Barbaro N.R. et al.High dietary salt-induced dendritic cell activation underlies microbial dysbiosis-associated hypertension.JCI Insight. 2019; 5e126241Google Scholar A possibility is that the production of proinflammatory IL-17 and interferon γ with sodium is driven by intestinal dendritic cell activation via isolevuglandins. Furthermore, excessive sodium intake depleted Lactobacillus murinus in mice, resulting in a higher number of T-helper 17 (Th17) cells in the spleen and intestinal lamina propria, likely via indole-3-lactic acid.19Wilck N. Matus M.G. Kearney S.M. et al.Salt-responsive gut commensal modulates T(H)17 axis and disease.Nature. 2017; 551: 585-589Crossref PubMed Scopus (752) Google Scholar Treatment with Lactobacillus spp. modestly decreased BP and the prevalence of Th17 cells in mice and healthy humans challenged with a high salt level.19Wilck N. Matus M.G. Kearney S.M. et al.Salt-responsive gut commensal modulates T(H)17 axis and disease.Nature. 2017; 551: 585-589Crossref PubMed Scopus (752) Google Scholar These studies did not measure19Wilck N. Matus M.G. Kearney S.M. et al.Salt-responsive gut commensal modulates T(H)17 axis and disease.Nature. 2017; 551: 585-589Crossref PubMed Scopus (752) Google Scholar or detect18Ferguson J.F. Aden L.A. Barbaro N.R. et al.High dietary salt-induced dendritic cell activation underlies microbial dysbiosis-associated hypertension.JCI Insight. 2019; 5e126241Google Scholar changes in kidney function or inflammation. However, other evidence suggests the existence of a gut–kidney axis that prevents and drives kidney inflammation. For example, interventions using fermentable fiber (which is digested by the microbiota) or direct treatment with short-chain fatty acids (SCFAs; produced by the microbiota during fiber fermentation) shifted the kidney transcriptome, with changes in inflammatory pathways such as IL-1β signalling.20Marques F.Z. Nelson E. Chu P.Y. et al.High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice.Circulation. 2017; 135: 964-977Crossref PubMed Scopus (595) Google Scholar SCFAs reach the systemic circulation, where they reduce BP in hypertensive animals20Marques F.Z. Nelson E. Chu P.Y. et al.High-fiber diet and acetate supplementation change the gut microbiota and prevent the development of hypertension and heart failure in hypertensive mice.Circulation. 2017; 135: 964-977Crossref PubMed Scopus (595) Google Scholar, 21Bartolomaeus H. Balogh A. Yakoub M. et al.Short-chain fatty acid propionate protects from hypertensive cardiovascular damage.Circulation. 2019; 139: 1407-1421Crossref PubMed Scopus (376) Google Scholar, 22Kaye D.M. Shihata W.A. Jama H.A. et al.Deficiency of prebiotic fiber and insufficient signaling through gut metabolite-sensing receptors leads to cardiovascular disease.Circulation. 2020; 141: 1393-1403Crossref PubMed Scopus (138) Google Scholar and patients.23Jama H.A. Rhys-Jones D. Nakai M. et al.Prebiotic intervention with HAMSAB in untreated essential hypertensive patients assessed in a phase II randomized trial.Nature Cardiovasc Res. 2023; 2: 35-43Crossref Scopus (10) Google Scholar They may act via reducing hypertension-associated inflammatory mechanisms, such as by priming T cells to differentiate into anti-inflammatory T regulatory cells.21Bartolomaeus H. Balogh A. Yakoub M. et al.Short-chain fatty acid propionate protects from hypertensive cardiovascular damage.Circulation. 2019; 139: 1407-1421Crossref PubMed Scopus (376) Google Scholar,22Kaye D.M. Shihata W.A. Jama H.A. et al.Deficiency of prebiotic fiber and insufficient signaling through gut metabolite-sensing receptors leads to cardiovascular disease.Circulation. 2020; 141: 1393-1403Crossref PubMed Scopus (138) Google Scholar,24Avery E.G. Bartolomaeus H. Rauch A. et al.Quantifying the impact of gut microbiota on inflammation and hypertensive organ damage.Cardiovasc Res. 2023; 119: 1441-1452Crossref PubMed Scopus (8) Google Scholar Alternatively, in the absence of SCFA-signaling via their G-protein–coupled receptors GPR41 and GPR43, the breakdown of the gut epithelial barrier allows passage of microbial-produced endotoxins such as lipopolysaccharides from the luminal gut into the systemic circulation.25Muralitharan RR, Zhegng T, Dinakis E, et al. GPR41/43 regulates blood pressure by improving gut epithelial barrier integrity to prevent TLR4 activation and renal inflammation. bioRxiv. Published online March 23, 2023. https://doi.org/10.1101/2023.03.20.533376.Google Scholar Lipopolysaccharide then binds to toll-like receptor 4 in macrophages, resulting in their migration to the kidney and the production of proinflammatory cytokines.25Muralitharan RR, Zhegng T, Dinakis E, et al. GPR41/43 regulates blood pressure by improving gut epithelial barrier integrity to prevent TLR4 activation and renal inflammation. bioRxiv. Published online March 23, 2023. https://doi.org/10.1101/2023.03.20.533376.Google Scholar An interesting notion is that sodium intake and SCFA levels may be inversely related. In a randomized clinical trial, aimed at reducing sodium intake over 6 weeks, a significant increase occurred in circulating SCFA levels, which was associated with a BP decrease, particularly in women.26Chen L. He F.J. Dong Y. et al.Modest sodium reduction increases circulating short-chain fatty acids in untreated hypertensives: a randomized, double-blind, placebo-controlled trial.Hypertension. 2020; 76: 73-79Crossref PubMed Scopus (49) Google Scholar In mice27Hamad I. Cardilli A. Corte-Real B.F. et al.High-salt diet induces depletion of lactic acid-producing bacteria in murine gut.Nutrients. 2022; 14: 1171Crossref PubMed Scopus (7) Google Scholar and a cohort study,28Nagase S. Karashima S. Tsujiguchi H. et al.Impact of gut microbiome on hypertensive patients with low-salt intake: Shika study results.Front Med (Lausanne). 2020; 7: 475Crossref PubMed Scopus (5) Google Scholar a high sodium level is associated with a reduction in abundance of bacteria associated with production of SCFAs. Regarding the therapeutic potential of SCFAs,23Jama H.A. Rhys-Jones D. Nakai M. et al.Prebiotic intervention with HAMSAB in untreated essential hypertensive patients assessed in a phase II randomized trial.Nature Cardiovasc Res. 2023; 2: 35-43Crossref Scopus (10) Google Scholar whether interventions with fermentable fiber and/or SCFAs can mitigate the detrimental interplay among sodium, gut microbiota, BP, and inflammation remains unclear. Another relevant interaction is the role of potassium in the gut microbiome. A cohort study of 2833 healthy Chinese participants whose dietary information was collected as 3-day, 24-hour recalls reported associations between 30 specific microbial taxa and potassium, and 54 that had a sodium-to-potassium ratio with a q value < 0.1.29Wang Y. Wang H. Howard A.G. et al.Associations of sodium and potassium consumption with the gut microbiota and host metabolites in a population-based study in Chinese adults.Am J Clin Nutr. 2020; 112: 1599-1612Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Many of these associations identified SCFA producers, such as Ruminococcus spp., Blautia, and other bacteria from the Lachnospiraceae family.29Wang Y. Wang H. Howard A.G. et al.Associations of sodium and potassium consumption with the gut microbiota and host metabolites in a population-based study in Chinese adults.Am J Clin Nutr. 2020; 112: 1599-1612Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Mice placed on a low-potassium diet for 28 days had increased markers of intestinal permeability and bacteria translocation from the gut to other sites (e.g., mesenteric lymph nodes).30Wu H. Huang R. Fan J. et al.Low potassium disrupt intestinal barrier and result in bacterial translocation.J Transl Med. 2022; 20: 309Crossref PubMed Scopus (4) Google Scholar An important point to consider is that certain types of food rich in fermentable fiber are also rich in potassium—for instance, green banana flour and beans—thereby being a confounding factor in some studies. Epigenetic mechanisms may play an important role in the development of SS hypertension. Epigenetic modifications via DNA methylation, histone modifications, microRNAs, or chromatin modifications respond to high-sodium intake by altering the expression of candidate genes, without changes in the underlying DNA sequence and their downstream signaling pathways, thus leading to SS hypertension.31Liu P. Liu Y. Liu H. et al.Role of DNA de novo (de)methylation in the kidney in salt-induced hypertension.Hypertension. 2018; 72: 1160-1171Crossref PubMed Scopus (23) Google Scholar,32Fujita T. Recent advances in hypertension: epigenetic mechanism involved in development of salt-sensitive hypertension.Hypertension. 2023; 80: 711-718Crossref PubMed Scopus (1) Google Scholar DNA methylation, a major type of epigenetic modification, may exhibit stable, long-lasting effects. In Dahl SS hypertension, de novo DNA methylation in the renal medulla contributed to the development of sodium-induced hypertension.31Liu P. Liu Y. Liu H. et al.Role of DNA de novo (de)methylation in the kidney in salt-induced hypertension.Hypertension. 2018; 72: 1160-1171Crossref PubMed Scopus (23) Google Scholar Renal expression of DNA methyltransferase 3a was higher in excessive sodium (4%)–fed Dahl SS rats, whereas no difference occurred in DNA methyltransferase 3a expression between rat strains on the low-salt diet. Moreover, hypermethylation of differentially methylated regions was specific to the infiltrating kidney T cells of Dahl SS rats on high-sodium intake.33Dasinger J.H. Alsheikh A.J. Abais-Battad J.M. et al.Epigenetic modifications in T cells: the role of DNA methylation in salt-sensitive hypertension.Hypertension. 2020; 75: 372-382Crossref PubMed Scopus (23) Google Scholar Inhibition of DNA methyltransferases blunted sodium-induced hypertension, associated with reduced immune-cell infiltration in the kidney, indicating that DNA methylation plays a functional role in SS hypertension. Environmental factors (e.g., nutrition and stress) during pregnancy contribute to the development of SS hypertension through epigenetic mechanisms. Aberrant DNA methylation contributes to prenatal programmed hypertension in offspring (F1) of pregnant mothers receiving a low-protein diet. Angiotensin II type 1a (AT1a) receptor gene DNA was undermethylated in the hypothalamus of offspring on a low-protein diet. This undermethylation was associated with reduced DNA methyltransferase 3a expression and activity and, in turn, increased hypothalamic AT1a receptor activity, leading to SS hypertension through kidney sympathetic overactivity (Figure 3).34Kawakami-Mori F. Nishimoto M. Reheman L. et al.Aberrant DNA methylation of hypothalamic angiotensin receptor in prenatal programmed hypertension.JCI Insight. 2018; 3e95625Crossref PubMed Scopus (22) Google Scholar Prenatal lipopolysaccharide exposure induces transgenerational transmission of SS hypertension by histone modification.35Cao N. Lan C. Chen C. et al.Prenatal lipopolysaccharides exposure induces transgenerational inheritance of hypertension.Circulation. 2022; 146: 1082-1095Crossref PubMed Scopus (6) Google Scholar H3K9me2 (an epigenetic modification to the DNA packaging protein histone H3) was downregulated in the kidneys of F4 and F5 offspring, and this was accompanied by reduced recruitment of H3K9me2 to the Ras-related C3 botulinum toxin substrate 1 (Rac1) promoter. Given that Rac1 is a potent activator of mineralocorticoid receptor (MR) signal transduction, sodium-induced activation of the Rac1–MR pathway leads to SS hypertension through impaired kidney sodium handling (Figure 3).35Cao N. Lan C. Chen C. et al.Prenatal lipopolysaccharides exposure induces transgenerational inheritance of hypertension.Circulation. 2022; 146: 1082-1095Crossref PubMed Scopus (6) Google Scholar,36Shibata S. Mu S. Kawarazaki H. et al.Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway.J Clin Invest. 2011; 121: 3233-3243Crossref PubMed Scopus (179) Google Scholar During the past few decades, the relationship among genes, epigenetic regulation, and age has been the focus of extensive research. Lysine-specific histone demethylase-1 (LSD1) is an epigenetic regulator of gene transcription that removes methyl groups from Lys4 and Lys9 of histone H3. LSD1 expression is modulated by dietary sodium intake; a high-sodium diet decreases the protein expression of LSD1 in mouse kidney. An LSD1 risk allele in humans and LSD1 deficiency (LSD1+/−) in mice led to increased salt sensitivity with aging and the development of SS hypertension in the elderly.37Krug A.W. Tille E. Sun B. et al.Lysine-specific demethylase-1 modifies the age effect on blood pressure sensitivity to dietary salt intake.Age (Dordr). 2013; 35: 1809-1820Crossref PubMed Scopus (13) Google Scholar,38Treesaranuwattana T. Wong K.Y.H. Brooks D.L. et al.Lysine-specific demethylase-1 deficiency increases agonist signaling via the mineralocorticoid receptor.Hypertension. 2020; 75: 1045-1053Crossref PubMed Scopus (8) Google Scholar LSD1+/− mice on high-sodium intake have hypertension, increased urinary potassium excretion, and increased levels and activation of MR, despite having reduced urinary aldosterone excretion. Treatment with the MR antagonist eplerenone improved hypertension and kaliuresis in these mice, suggesting that ligand-independent activation of MR is the underlying cause of this LSD1 deficiency–mediated phenotype.38Treesaranuwattana T. Wong K.Y.H. Brooks D.L. et al.Lysine-specific demethylase-1 deficiency increases agonist signaling via the mineralocorticoid receptor.Hypertension. 2020; 75: 1045-1053Crossref PubMed Scopus (8) Google Scholar According to the molecular mechanism by which LSD1 deficiency induces overactivation of the MR pathway, LSD1 has been postulated to act as a transcription repressor at H3K4 of the gene encoding MR, which can activate MR independently of aldosterone (Figure 3). Alpha-Klotho (Klotho), an anti-aging protein, is mainly produced in the kidney, and is secreted