Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Kidney and epigenetic mechanisms of salt-sensitive hypertension

Nature Reviews Nephrology volume 17, pages 350–363 (2021)Cite this article

Subjects

Abstract

Dietary salt intake increases blood pressure (BP) but the salt sensitivity of BP differs between individuals. The interplay of ageing, genetics and environmental factors, including malnutrition and stress, contributes to BP salt sensitivity. In adults, obesity is often associated with salt-sensitive hypertension. The children of women who experience malnutrition during pregnancy are at increased risk of developing obesity, diabetes and salt-sensitive hypertension as adults. Similarly, the offspring of mice that are fed a low-protein diet during pregnancy develop salt-sensitive hypertension in association with aberrant DNA methylation of the gene encoding type 1A angiotensin II receptor (AT1AR) in the hypothalamus, leading to upregulation of hypothalamic AT1AR and renal sympathetic overactivity. Ageing is also associated with salt-sensitive hypertension. In aged mice, promoter methylation leads to reduced kidney production of the anti-ageing factor Klotho and a decrease in circulating soluble Klotho. In the setting of Klotho deficiency, salt-induced activation of the vascular Wnt5a–RhoA pathway leads to ageing-associated salt-sensitive hypertension, potentially as a result of reduced renal blood flow and increased peripheral resistance. Thus, kidney mechanisms and aberrant DNA methylation of certain genes are involved in the development of salt-sensitive hypertension during fetal development and old age. Three distinct paradigms of epigenetic memory operate on different timescales in prenatal malnutrition, obesity and ageing.

Key points

  • Hyperaldosteronism induced by adipocyte-derived aldosterone-releasing factors, and renal sympathetic overactivity resulting from hypothalamic noradrenergic abnormalities, contribute to the development of obesity-induced salt-sensitive hypertension.

  • The offspring of mothers that experience malnutrition during pregnancy are at increased risk of developing salt-sensitive hypertension in adult life.

  • Aberrant DNA methylation of type 1 angiotensin II receptors in the hypothalamus contributes to prenatal programmed hypertension through salt-induced activation of the hypothalamic renal sympathetic nervous system.

  • An increase in the salt sensitivity of blood pressure with ageing contributes to the high prevalence of hypertension in elderly people.

  • A reduction in circulating Klotho owing to DNA methylation of Klotho in the kidney has a critical role in ageing-associated salt-sensitive hypertension through salt-induced activation of the non-canonical Wnt5a–RhoA pathway in the vasculature and a resulting reduction in renal blood flow.

  • Epigenetic modulation has a role in salt-sensitive hypertension throughout life, including as a result of malnutrition during pregnancy, obesity in adults and ageing.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Mechanisms of obesity-induced salt-sensitive hypertension.
Fig. 2: The epigenetic mechanism of prenatal programmed hypertension.
Fig. 3: Potential mechanisms of ageing-associated salt-sensitive hypertension.
Fig. 4: Epigenetic modulation in salt-sensitive hypertension.

Similar content being viewed by others

References

  1. World Health Organization. Hypertension. WHO https://www.who.int/news-room/fact-sheets/detail/hypertension (2019).

  2. Zhou, B. et al. Long-term and recent trends in hypertension awareness, treatment, and control in 12 high-income countries: an analysis of 123 nationally representative surveys. Lancet 394, 639–651 (2019).

    Article  Google Scholar 

  3. Bromfield, S. & Muntner, P. High blood pressure: the leading global burden of disease risk factor and the need for worldwide prevention programs. Curr. Hypertens. Rep. 15, 134–136 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Meneely, G. R. & Dahl, L. K. Electrolytes in hypertension: the effects of sodium chloride: the evidence from animal and human studies. Med. Clin. North. Am. 45, 271–283 (1961).

    Article  CAS  PubMed  Google Scholar 

  5. Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. Intersalt Cooperative Research Group. BMJ 297, 319–328 (1988).

    Article  Google Scholar 

  6. Mente, A. et al. Association of urinary sodium and potassium excretion with blood pressure. N. Engl. J. Med. 371, 601–611 (2014).

    Article  PubMed  CAS  Google Scholar 

  7. Luft, F. C. & Weinberger, M. H. Heterogeneous responses to changes in dietary salt intake: the salt-sensitivity paradigm. Am. J. Clin. Nutr. 65, 612S–617S (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Kawasaki, T., Delea, C. S., Bartter, F. C. & Smith, H. The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension. Am. J. Med. 64, 193–198 (1978).

    Article  CAS  PubMed  Google Scholar 

  9. Fujita, T., Henry, W. L., Bartter, F. C., Lake, C. R. & Delea, C. S. Factors influencing blood pressure in salt-sensitive patients with hypertension. Am. J. Med. 69, 334–344 (1980).

    Article  CAS  PubMed  Google Scholar 

  10. Guyton, A. C. Kidneys and fluids in pressure regulation. Small volume but large pressure changes. Hypertension 19, I2–I8 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. Hall, J. E., Guyton, A. C. & Brands, M. W. Pressure-volume regulation in hypertension. Kidney Int. Suppl. 55, S35–S41 (1996).

    CAS  PubMed  Google Scholar 

  12. Guyton, A. C. The surprising kidney-fluid mechanism for pressure control — its infinite gain! Hypertension 16, 725–730 (1990).

    Article  CAS  PubMed  Google Scholar 

  13. Hall, J. E. Mechanisms of abnormal renal sodium handling in obesity hypertension. Am. J. Hypertens. 10, 49S–55S (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ. Res. 116, 991–1006 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Edwards, A. & McDonough, A. A. Impact of angiotensin II-mediated stimulation of sodium transporters in the nephron assessed by computational modeling. Am. J. Physiol. Renal Physiol. 317, F1656–F1668 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhao, D., Seth, D. M. & Navar, L. G. Enhanced distal nephron sodium reabsorption in chronic angiotensin II-infused mice. Hypertension 54, 120–126 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Riazi, S., Khan, O., Hu, X. & Ecelbarger, C. A. Aldosterone infusion with high-NaCl diet increases blood pressure in obese but not lean Zucker rats. Am. J. Physiol. Renal Physiol. 291, F597–F605 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Winternitz, S. R., Katholi, R. E. & Oparil, S. Role of the renal sympathetic nerves in the development and maintenance of hypertension in the spontaneously hypertensive rat. J. Clin. Invest. 66, 971–978 (1980).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shibata, S. et al. Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway. J. Clin. Invest. 121, 3233–3243 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mu, S. et al. Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nat. Med. 17, 573–580 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Coffman, T. M. Under pressure: the search for the essential mechanisms of hypertension. Nat. Med. 17, 1402–1409 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Fujita, T., Noda, H. & Ando, K. Sodium susceptibility and potassium effects in young patients with borderline hypertension. Circulation 69, 468–476 (1984).

    Article  CAS  PubMed  Google Scholar 

  23. Sullivan, J. M., Prewitt, R. L., Ratts, T. E., Josephs, J. A. & Connor, M. J. Hemodynamic characteristics of sodium-sensitive human subjects. Hypertension 9, 398–406 (1987).

    Article  CAS  PubMed  Google Scholar 

  24. Morris, R. C. Jr., Schmidlin, O., Sebastian, A., Tanaka, M. & Kurtz, T. W. Vasodysfunction that involves renal vasodysfunction, not abnormally increased renal retention of sodium, accounts for the initiation of salt-induced hypertension. Circulation 133, 881–893 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Redgrave, J., Rabinowe, S., Hollenberg, N. K. & Williams, G. H. Correction of abnormal renal blood flow response to angiotensin II by converting enzyme inhibition in essential hypertensives. J. Clin. Invest. 75, 1285–1290 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Campese, V. M., Parise, M., Karubian, F. & Bigazzi, R. Abnormal renal hemodynamics in black salt-sensitive patients with hypertension. Hypertension 18, 805–812 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. Fujita, T., Ando, K. & Ogata, E. Systemic and regional hemodynamics in patients with salt-sensitive hypertension. Hypertension 16, 235–244 (1990).

    Article  CAS  PubMed  Google Scholar 

  28. Polichnowski, A. J., Griffin, K. A., Long, J., Williamson, G. A. & Bidani, A. K. Blood pressure-renal blood flow relationships in conscious angiotensin II- and phenylephrine-infused rats. Am. J. Physiol. Renal Physiol. 305, F1074–F1084 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Oliver, J. A. & Cannon, P. J. The effect of altered sodium balance upon renal vascular reactivity to angiotensin II and norepinephrine in the dog. Mechanism of variation in angiotensin responses. J. Clin. Invest. 61, 610–623 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Crowley, S. D. et al. Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney. Proc. Natl Acad. Sci. USA 103, 17985–17990 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. El-Osta, A. et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J. Exp. Med. 205, 2409–2417 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kazmi, N. et al. Associations between high blood pressure and DNA methylation. PLoS ONE 15, e0227728 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Li, Y. et al. The DNA methylome of human peripheral blood mononuclear cells. PLoS Biol. 8, e1000533 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Friso, S., Carvajal, C. A., Fardella, C. E. & Olivieri, O. Epigenetics and arterial hypertension: the challenge of emerging evidence. Transl Res. 165, 154–165 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Liu, P. et al. Role of DNA de novo (de)methylation in the kidney in dalt-induced hypertension. Hypertension 72, 1160–1171 (2018).

    Article  CAS  PubMed  Google Scholar 

  36. Dasinger, J. H. et al. Epigenetic modifications in T cells. Hypertension 75, 372–382 (2020).

    Article  CAS  PubMed  Google Scholar 

  37. Garrison, R. J., Kannel, W. B., Stokes, J. & Castelli, W. P. Incidence and precursors of hypertension in young adults: the Framingham offspring study. Prev. Med. 16, 235–251 (1987).

    Article  CAS  PubMed  Google Scholar 

  38. Rocchini, A. P. et al. The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N. Engl. J. Med. 321, 580–585 (1989).

    Article  CAS  PubMed  Google Scholar 

  39. Chen, J. et al. Metabolic syndrome and salt sensitivity of blood pressure in non-diabetic people in China: a dietary intervention study. Lancet 373, 829–835 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tuck, M. L., Sowers, J., Dornfeld, L., Kledzik, G. & Maxwell, M. The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients. N. Engl. J. Med. 304, 930–933 (1981).

    Article  CAS  PubMed  Google Scholar 

  41. Rocchini, A. P., Katch, V. L., Grekin, R., Moorehead, C. & Anderson, J. Role for aldosterone in blood pressure regulation of obese adolescents. Am. J. Cardiol. 57, 613–618 (1986).

    Article  CAS  PubMed  Google Scholar 

  42. Rossi, G. P. et al. Body mass index predicts plasma aldosterone concentrations in overweight-obese primary hypertensive patients. J. Clin. Endocrinol. Metab. 93, 2566–2571 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. de Paula, R. B., da Silva, A. A. & Hall, J. E. Aldosterone antagonism attenuates obesity-induced hypertension and glomerular hyperfiltration. Hypertension 43, 41–47 (2004).

    Article  PubMed  CAS  Google Scholar 

  44. Engeli, S. et al. Weight loss and the renin-angiotensin-aldosterone system. Hypertension 45, 356–362 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Kidambi, S. et al. Association of adrenal steroids with hypertension and the metabolic syndrome in blacks. Hypertension 49, 704–711 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Ehrhart-Bornstein, M. et al. Human adipocytes secrete mineralocorticoid-releasing factors. Proc. Natl Acad. Sci. USA 100, 14211–14216 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Goodfriend, T. L., Ball, D. L., Egan, B. M., Campbell, W. B. & Nithipatikom, K. Epoxy-keto derivative of linoleic acid stimulates aldosterone secretion. Hypertension 43, 358–363 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Wong, G. W., Wang, J., Hug, C., Tsao, T. S. & Lodish, H. F. A family of Acrp30/adiponectin structural and functional paralogs. Proc. Natl Acad. Sci. USA 101, 10302–10307 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Huby, A. C. et al. Adipocyte-derived hormone leptin is a direct regulator of aldosterone secretion, which promotes endothelial dysfunction and cardiac fibrosis. Circulation 132, 2134–2145 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Nagase, M. et al. Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors. J. Am. Soc. Nephrol. 17, 3438–3446 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Matsui, H. et al. Salt excess causes left ventricular diastolic dysfunction in rats with metabolic disorder. Hypertension 52, 287–294 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Nagase, M., Matsui, H., Shibata, S., Gotoda, T. & Fujita, T. Salt-induced nephropathy in obese spontaneously hypertensive rats via paradoxical activation of the mineralocorticoid receptor: role of oxidative stress. Hypertension 50, 877–883 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Kawarazaki, W. et al. Angiotensin II- and salt-induced kidney injury through Rac1-mediated mineralocorticoid receptor activation. J. Am. Soc. Nephrol. 23, 997–1007 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kawarazaki, W. & Fujita, T. The role of aldosterone in obesity-related hypertension. Am. J. Hypertens. 29, 415–423 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Fujita, T. Mechanism of salt-sensitive hypertension: focus on adrenal and sympathetic nervous systems. J. Am. Soc. Nephrol. 25, 1148–1155 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Briones, A. M. et al. Adipocytes produce aldosterone through calcineurin-dependent signaling pathways: implications in diabetes mellitus-associated obesity and vascular dysfunction. Hypertension 59, 1069–1078 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Shibata, S. et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat. Med. 14, 1370–1376 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Van Beusecum, J. P. et al. High salt activates CD11c+ antigen-presenting cells via SGK (serum glucocorticoid kinase) 1 to promote renal inflammation and salt-sensitive hypertension. Hypertension 74, 555–563 (2019).

    Article  PubMed  CAS  Google Scholar 

  59. Yoshida, S. et al. Local mineralocorticoid receptor activation and the role of Rac1 in obesity-related diabetic kidney disease. Nephron Exp. Nephrol. 126, 16–24 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Ando, K. et al. Anti-albuminuric effect of the aldosterone blocker eplerenone in non-diabetic hypertensive patients with albuminuria: a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2, 944–953 (2014).

    Article  CAS  PubMed  Google Scholar 

  61. Nishimoto, M. et al. Mineralocorticoid receptor blockade suppresses dietary salt-induced ACEI/ARB-resistant albuminuria in non-diabetic hypertension: a sub-analysis of evaluate study. Hypertens. Res. 42, 514–521 (2019).

    Article  CAS  PubMed  Google Scholar 

  62. Hall, J. E. The kidney, hypertension, and obesity. Hypertension 41, 625–633 (2003).

    Article  PubMed  CAS  Google Scholar 

  63. Hall, J. E., Do Carmo, J. M., Da Silva, A. A., Wang, Z. & Hall, M. E. Obesity, kidney dysfunction and hypertension: mechanistic links. Nat. Rev. Nephrol. 15, 367–385 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Prior, L. J. et al. Exposure to a high-fat diet alters leptin sensitivity and elevates renal sympathetic nerve activity and arterial pressure in rabbits. Hypertension 55, 862–868 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Nagae, A. et al. Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in obesity-induced hypertension. Circulation 119, 978–986 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Grassi, G. et al. Sympathetic activation in obese normotensive subjects. Hypertension 25, 560–563 (1995).

    Article  CAS  PubMed  Google Scholar 

  67. Vaz, M. et al. Regional sympathetic nervous activity and oxygen consumption in obese normotensive human subjects. Circulation 96, 3423–3429 (1997).

    Article  CAS  PubMed  Google Scholar 

  68. Lohmeier, T. E. et al. Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension 59, 331–338 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. DiBona, G. F. Physiology in perspective: the wisdom of the body. Neural control of the kidney. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R633–R641 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Hesse, I. F. & Johns, E. J. The role of alpha-adrenoceptors in the regulation of renal tubular sodium reabsorption and renin secretion in the rabbit. Br. J. Pharmacol. 84, 715–724 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Terker, A. S. et al. Sympathetic stimulation of thiazide-sensitive sodium chloride cotransport in the generation of salt-sensitive hypertension. Hypertension 64, 178–184 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Castañeda-Bueno, M. et al. Activation of the renal Na+:Cl− cotransporter by angiotensin II is a WNK4-dependent process. Proc. Natl Acad. Sci. USA 109, 7929–7934 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  73. San-Cristobal, P. et al. Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway. Proc. Natl Acad. Sci. USA 106, 4384–4389 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Davies, M. R. et al. The thiazide-sensitive co-transporter promotes the development of sodium retention in mice with diet-induced obesity. Kidney Blood Press. Res. 40, 509–519 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. Kassab, S. et al. Renal denervation attenuates the sodium retention and hypertension associated with obesity. Hypertension 25, 893–897 (1995).

    Article  CAS  PubMed  Google Scholar 

  76. Henegar, J. R. et al. Catheter-based radiorefrequency renal denervation lowers blood pressure in obese hypertensive dogs. Am. J. Hypertens. 27, 1285–1292 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Katayama, T. et al. Long-term renal denervation normalizes disrupted blood pressure circadian rhythm and ameliorates cardiovascular injury in a rat model of metabolic syndrome. J. Am. Heart Assoc. 2, e000197 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Komers, R. et al. Enhanced phosphorylation of Na+-Cl− co-transporter in experimental metabolic syndrome: role of insulin. Clin. Sci. 123, 635–647 (2012).

    Article  CAS  Google Scholar 

  79. Nishida, H. et al. Phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice. Hypertension 60, 981–990 (2012).

    Article  CAS  PubMed  Google Scholar 

  80. Brands, M. W. & Hall, J. E. Insulin resistance, hyperinsulinemia, and obesity-associated hypertension. J. Am. Soc. Nephrol. 3, 1064–1077 (1992).

    Article  CAS  PubMed  Google Scholar 

  81. Hall, J. E. et al. Hemodynamic and renal responses to chronic hyperinsulinemia in obese, insulin-resistant dogs. Hypertension 25, 994–1002 (1995).

    Article  CAS  PubMed  Google Scholar 

  82. Koepke, J. P. & DiBona, G. F. High sodium intake enhances renal nerve and antinatriuretic responses to stress in spontaneously hypertensive rats. Hypertension 7, 357–363 (1985).

    Article  CAS  PubMed  Google Scholar 

  83. Fujita, T. & Sato, Y. Changes in renal and central noradrenergic activity with potassium in DOCA-salt rats. Am. J. Physiol. 246, F670–F675 (1984).

    CAS  PubMed  Google Scholar 

  84. Fujita, T. & Sato, Y. Hypotensive effect of taurine. Possible involvement of the sympathetic nervous system and endogenous opiates. J. Clin. Invest. 82, 993–997 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Sato, Y., Ando, K., Ogata, E. & Fujita, T. High potassium intake attenuates antinatriuretic response to air stress in DOCA-salt rats. Am. J. Physiol. 260, R941–R945 (1991).

    CAS  PubMed  Google Scholar 

  86. Bell, B. B. & Rahmouni, K. Leptin as a mediator of obesity-induced hypertension. Curr. Obes. Rep. 5, 397–404 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Morgan, D. A., Thedens, D. R., Weiss, R. & Rahmouni, K. Mechanisms mediating renal sympathetic activation to leptin in obesity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295, R1730–R1736 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Purkayastha, S., Zhang, G. & Cai, D. Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB. Nat. Med. 17, 883–887 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. do Carmo, J. M. et al. Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons. Hypertension 57, 918–926 (2011).

    Article  PubMed  CAS  Google Scholar 

  90. Xue, B. et al. Leptin mediates high-fat diet sensitization of angiotensin II-elicited hypertension by upregulating the brain renin–angiotensin system and inflammation. Hypertension 67, 970–976 (2016).

    Article  CAS  PubMed  Google Scholar 

  91. Xue, B. et al. Central renin-angiotensin system activation and inflammation induced by high-fat diet sensitize angiotensin II-elicited hypertension. Hypertension 67, 163–170 (2016).

    Article  CAS  PubMed  Google Scholar 

  92. De Kloet, A. D. et al. Neuroimmune communication in hypertension and obesity: a new therapeutic angle? Pharmacol. Ther. 138, 428–440 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. De Kloet, A. D. et al. Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity. J. Neurosci. 33, 4825–4833 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Fujita, M., Ando, K., Nagae, A. & Fujita, T. Sympathoexcitation by oxidative stress in the brain mediates arterial pressure elevation in salt-sensitive hypertension. Hypertension 50, 360–367 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Choi, J. et al. Role of the histone deacetylase inhibitor valproic acid in high-fat diet-induced hypertension via inhibition of HDAC1/angiotensin II axis. Int. J. Obes. 41, 1702–1709 (2017).

    Article  CAS  Google Scholar 

  96. Kawakami-Mori, F. et al. Aberrant DNA methylation of hypothalamic angiotensin receptor in prenatal programmed hypertension. JCI Insight 3, e95625 (2018).

    Article  PubMed Central  Google Scholar 

  97. Boström, A. E. et al. Longitudinal genome-wide methylation study of Roux-en-Y gastric bypass patients reveals novel CpG sites associated with essential hypertension. BMC Med. Genomics 9, 20 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Barker, D. J., Osmond, C., Golding, J., Kuh, D. & Wadsworth, M. E. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 298, 564–567 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Gluckman, P. D. Living with the past: evolution, development, and patterns of disease. Science 305, 1733–1736 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Bateson, P. et al. Developmental plasticity and human health. Nature 430, 419–421 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Hanson, M. A. & Gluckman, P. D. Early developmental conditioning of later health and disease: physiology or pathophysiology? Physiol. Rev. 94, 1027–1076 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Vehaskari, V. M. & Woods, L. L. Prenatal programming of hypertension: lessons from experimental models. J. Am. Soc. Nephrol. 16, 2545–2556 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Seckl, J. R. Glucocorticoids, feto-placental 11 beta-hydroxysteroid dehydrogenase type 2, and the early life origins of adult disease. Steroids 62, 89–94 (1997).

    Article  CAS  PubMed  Google Scholar 

  104. Ortiz, L. A., Quan, A., Zarzar, F., Weinberg, A. & Baum, M. Prenatal dexamethasone programs hypertension and renal injury in the rat. Hypertension 41, 328–334 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Sheen, J.-M. et al. Prenatal dexamethasone-induced programmed hypertension and renal programming. Life Sci. 132, 41–48 (2015).

    Article  CAS  PubMed  Google Scholar 

  106. Manning, J. & Vehaskari, V. M. Postnatal modulation of prenatally programmed hypertension by dietary Na and ACE inhibition. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R80–R84 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Tang, J. I., Kenyon, C. J., Seckl, J. R. & Nyirenda, M. J. Prenatal overexposure to glucocorticoids programs renal 11β-hydroxysteroid dehydrogenase type 2 expression and salt-sensitive hypertension in the rat. J. Hypertens. 29, 282–289 (2011).

    Article  CAS  PubMed  Google Scholar 

  108. Baum, M. Role of renal sympathetic nerve activity in prenatal programming of hypertension. Pediatr. Nephrol. 33, 409–419 (2018).

    Article  PubMed  Google Scholar 

  109. Dagan, A., Kwon, H. M., Dwarakanath, V. & Baum, M. Effect of renal denervation on prenatal programming of hypertension and renal tubular transporter abundance. Am. J. Physiol. Renal Physiol. 295, F29–F34 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Mizuno, M., Lozano, G., Siddique, K., Baum, M. & Smith, S. A. Enalapril attenuates the exaggerated sympathetic response to physical stress in prenatally programmed hypertensive rats. Hypertension 63, 324–329 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Mizuno, M., Siddique, K., Baum, M. & Smith, S. A. Prenatal programming of hypertension induces sympathetic overactivity in response to physical stress. Hypertension 61, 180–186 (2013).

    Article  CAS  PubMed  Google Scholar 

  112. Pladys, P. et al. Role of brain and peripheral angiotensin II in hypertension and altered arterial baroreflex programmed during fetal life in rat. Pediatr. Res. 55, 1042–1049 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Li, P. et al. Role of paraventricular angiotensin AT1 receptors in salt-sensitive hypertension in mRen-2 transgenic rats. Am. J. Physiol. 270, R1178–R1181 (1996).

    CAS  PubMed  Google Scholar 

  114. Senanayake, P. D. et al. Increased expression of angiotensin peptides in the brain of transgenic hypertensive rats. Peptides 15, 919–926 (1994).

    Article  CAS  PubMed  Google Scholar 

  115. De Kloet, A. D. et al. A unique “angiotensin-sensitive” neuronal population coordinates neuroendocrine, cardiovascular, and behavioral responses to stress. J. Neurosci. 37, 3478–3490 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Aguilera, G., Kiss, A. & Luo, X. Increased expression of type 1 angiotensin II receptors in the hypothalamic paraventricular nucleus following stress and glucocorticoid administration. J. Neuroendocrinol. 7, 775–783 (1995).

    Article  CAS  PubMed  Google Scholar 

  117. Treviño, L. S. et al. Epigenome environment interactions accelerate epigenomic aging and unlock metabolically restricted epigenetic reprogramming in adulthood. Nat. Commun. 11, 2316 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Nenke, M. A. et al. Differential effects of estrogen on corticosteroid-binding globulin forms suggests reduced cleavage in pregnancy. J. Endocr. Soc. 1, 202–210 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Stern, J. E. et al. Astrocytes contribute to angiotensin II stimulation of hypothalamic neuronal activity and sympathetic outflow. Hypertension 68, 1483–1493 (2016).

    Article  CAS  PubMed  Google Scholar 

  121. Liu, G. et al. Angiotensin II induces human astrocyte senescence through reactive oxygen species production. Hypertens. Res. 34, 479–483 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. Cruz, J. C., Flôr, A. F., França-Silva, M. S., Balarini, C. M. & Braga, V. A. Reactive oxygen species in the paraventricular nucleus of the hypothalamus alter sympathetic activity during metabolic syndrome. Front. Physiol. 6, 384 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Rodríguez-Rodríguez, P. et al. Fetal undernutrition is associated with perinatal sex-dependent alterations in oxidative status. J. Nutr. Biochem. 26, 1650–1659 (2015).

    Article  PubMed  CAS  Google Scholar 

  124. De Sousa, S. M. et al. Oxidative injuries induced by maternal low-protein diet in female brainstem. Nutr. Neurosci. 21, 580–588 (2017).

    Article  PubMed  Google Scholar 

  125. de Brito Alves, J. L. et al. Maternal protein restriction induced-hypertension is associated to oxidative disruption at transcriptional and functional levels in the medulla oblongata. Clin. Exp. Pharmacol. Physiol. 43, 1177–1184 (2016).

    Article  PubMed  CAS  Google Scholar 

  126. Ojeda, N. B., Grigore, D., Robertson, E. B. & Alexander, B. T. Estrogen protects against increased blood pressure in postpubertal female growth restricted offspring. Hypertension 50, 679–685 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Dasinger, J. H., Davis, G. K., Newsome, A. D. & Alexander, B. T. Developmental programming of hypertension: physiological mechanisms. Hypertension 68, 826–831 (2016).

    Article  CAS  PubMed  Google Scholar 

  128. He, F. et al. Association between DNA methylation in obesity-related genes and body mass index percentile in adolescents. Sci. Rep. 9, 2079 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Kohno, D. et al. Dnmt3a in Sim1 neurons is necessary for normal energy homeostasis. J. Neurosci. 34, 15288–15296 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Forrester, S. J., Kikuchi, D. S., Hernandes, M. S., Xu, Q. & Griendling, K. K. Reactive oxygen species in metabolic and inflammatory signaling. Circ. Res. 122, 877–902 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Guarino, D., Nannipieri, M., Iervasi, G., Taddei, S. & Bruno, R. M. The role of the autonomic nervous system in the pathophysiology of obesity. Front. Physiol. 8, 665 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Mahbouli, S. et al. Leptin induces ROS via NOX5 in healthy and neoplastic mammary epithelial cells. Oncol. Rep. 38, 3254–3264 (2017).

    Article  CAS  PubMed  Google Scholar 

  133. Wolf-Maier, K. et al. Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA 289, 2363–2369 (2003).

    Article  PubMed  Google Scholar 

  134. Lim, S. S. et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2224–2260 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Beckett, N. S. et al. Treatment of hypertension in patients 80 years of age or older. N. Engl. J. Med. 358, 1887–1898 (2008).

    Article  CAS  PubMed  Google Scholar 

  136. Luft, F. C., Grim, C. E., Fineberg, N. & Weinberger, M. C. Effects of volume expansion and contraction in normotensive whites, blacks, and subjects of different ages. Circulation 59, 643–650 (1979).

    Article  CAS  PubMed  Google Scholar 

  137. Weinberger, M. H. & Fineberg, N. S. Sodium and volume sensitivity of blood pressure. Age and pressure change over time. Hypertension 18, 67–71 (1991).

    Article  CAS  PubMed  Google Scholar 

  138. Elijovich, F. et al. Salt sensitivity of blood pressure: a scientific statement from the American Heart Association. Hypertension 68, e7–e46 (2016).

    Article  CAS  PubMed  Google Scholar 

  139. Oliver, W. J., Cohen, E. L. & Neel, J. V. Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a “no-salt” culture. Circulation 52, 146–151 (1975).

    Article  CAS  PubMed  Google Scholar 

  140. Fliser, D. et al. Renal function in the elderly: impact of hypertension and cardiac function. Kidney Int. 51, 1196–1204 (1997).

    Article  CAS  PubMed  Google Scholar 

  141. Knox, F. G., Mertz, J. I., Burnett, J. C. Jr. & Haramati, A. Role of hydrostatic and oncotic pressures in renal sodium reabsorption. Circ. Res. 52, 491–500 (1983).

    Article  CAS  PubMed  Google Scholar 

  142. Shimamoto, H. & Shimamoto, Y. Time course of hemodynamic responses to sodium in elderly hypertensive patients. Hypertension 16, 387–397 (1990).

    Article  CAS  PubMed  Google Scholar 

  143. Hill, C., Lateef, A. M., Engels, K., Samsell, L. & Baylis, C. Basal and stimulated nitric oxide in control of kidney function in the aging rat. Am. J. Physiol. 272, R1747–R1753 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. De Nicola, L., Blantz, R. C. & Gabbai, F. B. Nitric oxide and angiotensin II. Glomerular and tubular interaction in the rat. J. Clin. Invest. 89, 1248–1256 (1992).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Zhou, X. J., Vaziri, N. D., Zhang, J., Wang, H. W. & Wang, X. Q. Association of renal injury with nitric oxide deficiency in aged SHR: prevention by hypertension control with AT1 blockade. Kidney Int. 62, 914–921 (2002).

    Article  CAS  PubMed  Google Scholar 

  146. Brown, J. M. et al. Aldosterone dysregulation with aging predicts renal vascular function and cardiovascular risk. Hypertension 63, 1205–1211 (2014).

    Article  CAS  PubMed  Google Scholar 

  147. Nanba, K. et al. Age-related autonomous aldosteronism. Circulation 136, 347–355 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Arnold, A. C. et al. Mineralocorticoid receptor activation contributes to the supine hypertension of autonomic failure. Hypertension 67, 424–429 (2016).

    Article  CAS  PubMed  Google Scholar 

  149. Ayuzawa, N. et al. Rac1-mediated activation of mineralocorticoid receptor in pressure overload-induced cardiac injury. Hypertension 67, 99–106 (2016).

    Article  CAS  PubMed  Google Scholar 

  150. Bauersachs, J., Jaisser, F. & Toto, R. Mineralocorticoid receptor activation and mineralocorticoid receptor antagonist treatment in cardiac and renal diseases. Hypertension 65, 257–263 (2015).

    Article  CAS  PubMed  Google Scholar 

  151. Bender, S. B. et al. Mineralocorticoid receptor antagonism treats obesity-associated cardiac diastolic dysfunction. Hypertension 65, 1082–1088 (2015).

    Article  CAS  PubMed  Google Scholar 

  152. Jia, G. et al. Endothelial mineralocorticoid receptor deletion prevents diet-induced cardiac diastolic dysfunction in females. Hypertension 66, 1159–1167 (2015).

    Article  CAS  PubMed  Google Scholar 

  153. McCurley, A. et al. Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat. Med. 18, 1429–1433 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Kim, S. K. et al. Smooth muscle cell–mineralocorticoid receptor as a mediator of cardiovascular stiffness with aging. Hypertension 71, 609–621 (2018).

    Article  CAS  PubMed  Google Scholar 

  155. DuPont, J. J. et al. Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging. JCI Insight 1, e88942 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Köttgen, A. et al. Multiple loci associated with indices of renal function and chronic kidney disease. Nat. Genet. 41, 712–717 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Mutig, K. et al. Activation of the bumetanide-sensitive Na+,K+,2Cl− cotransporter (NKCC2) is facilitated by Tamm-Horsfall protein in a chloride-sensitive manner. J. Biol. Chem. 286, 30200–30210 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Trudu, M. et al. Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression. Nat. Med. 19, 1655–1660 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Guzik, T. J. & Touyz, R. M. Oxidative stress, inflammation, and vascular aging in hypertension. Hypertension 70, 660–667 (2017).

    Article  CAS  PubMed  Google Scholar 

  160. Wirth, A. et al. Age-dependent blood pressure elevation is due to increased vascular smooth muscle tone mediated by G-protein signalling. Cardiovasc. Res. 109, 131–140 (2016).

    Article  CAS  PubMed  Google Scholar 

  161. Dominguez, L. J. & Barbagallo, M. The biology of the metabolic syndrome and aging. Curr. Opin. Clin. Nutr. Metab. Care 19, 5–11 (2016).

    Article  CAS  PubMed  Google Scholar 

  162. Bonomini, F., Rodella, L. F. & Rezzani, R. Metabolic syndrome, aging and involvement of oxidative stress. Aging Dis. 6, 109 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Sato, Y. & Yanagita, M. Immunology of the ageing kidney. Nat. Rev. Nephrol. 15, 625–640 (2019).

    Article  PubMed  Google Scholar 

  165. Barnes, J. N. et al. Aging enhances autonomic support of blood pressure in women. Hypertension 63, 303–308 (2014).

    Article  CAS  PubMed  Google Scholar 

  166. Zubcevic, J. et al. Altered inflammatory response is associated with an impaired autonomic input to the bone marrow in the spontaneously hypertensive rat. Hypertension 63, 542–550 (2014).

    Article  CAS  PubMed  Google Scholar 

  167. López-Andrés, N. et al. Absence of cardiotrophin 1 is associated with decreased age-dependent arterial stiffness and increased longevity in mice. Hypertension 61, 120–129 (2013).

    Article  PubMed  CAS  Google Scholar 

  168. Seals, D. R., Jablonski, K. L. & Donato, A. J. Aging and vascular endothelial function in humans. Clin. Sci. 120, 357–375 (2011).

    Article  CAS  Google Scholar 

  169. Cao, W. et al. Sympathetic overactivity in CKD disrupts buffering of neurotransmission by endothelium-derived hyperpolarizing factor and enhances vasoconstriction. J. Am. Soc. Nephrol. 31, 2312–2325 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. El Assar, M. et al. Mechanisms involved in the aging-induced vascular dysfunction. Front. Physiol. 3, 132 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Thompson, R. F., Fazzari, M. J. & Greally, J. M. Experimental approaches to the study of epigenomic dysregulation in ageing. Exp. Gerontol. 45, 255–268 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

    Article  CAS  PubMed  Google Scholar 

  173. Williams, J. S. et al. Lysine-specific demethylase 1: an epigenetic regulator of salt-sensitive hypertension. Am. J. Hypertens. 25, 812–817 (2012).

    Article  CAS  PubMed  Google Scholar 

  174. Krug, A. W. et al. Lysine-specific demethylase-1 modifies the age effect on blood pressure sensitivity to dietary salt intake. Age 35, 1809–1820 (2013).

    Article  CAS  PubMed  Google Scholar 

  175. Treesaranuwattana, T. et al. Lysine-specific demethylase-1 deficiency increases agonist signaling via the mineralocorticoid receptor. Hypertension 75, 1045–1053 (2020).

    Article  CAS  PubMed  Google Scholar 

  176. Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51 (1997).

    Article  CAS  PubMed  Google Scholar 

  177. Kurosu, H. et al. Suppression of aging in mice by the hormone Klotho. Science 309, 1829–1833 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Zhou, X., Chen, K., Lei, H. & Sun, Z. Klotho gene deficiency causes salt-sensitive hypertension via monocyte chemotactic protein-1/CC chemokine receptor 2-mediated inflammation. J. Am. Soc. Nephrol. 26, 121–132 (2015).

    Article  CAS  PubMed  Google Scholar 

  179. Liu, Y. et al. CD8+ T cells stimulate Na-Cl co-transporter NCC in distal convoluted tubules leading to salt-sensitive hypertension. Nat. Commun. 8, 14037 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Koyama, D. et al. Soluble alpha Klotho as a candidate for the biomarker of aging. Biochem. Biophys. Res. Commun. 467, 1019–1025 (2015).

    Article  CAS  PubMed  Google Scholar 

  181. Xiao, N. M., Zhang, Y. M., Zheng, Q. & Gu, J. Klotho is a serum factor related to human aging. Chin. Med. J. 117, 742–747 (2004).

    CAS  PubMed  Google Scholar 

  182. Citterio, L. et al. Klotho gene in human salt-sensitive hypertension. Clin. J. Am. Soc. Nephrol. 15, 375–383 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Kawarazaki, W. et al. Salt causes aging-associated hypertension via vascular Wnt5a under Klotho deficiency. J. Clin. Invest. 130, 4152–4166 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Foulquier, S. et al. WNT signaling in cardiac and vascular disease. Pharmacol. Rev. 70, 68–141 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Liu, H. et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317, 803–806 (2007).

    Article  CAS  PubMed  Google Scholar 

  186. Niehrs, C. The complex world of WNT receptor signalling. Nat. Rev. Mol. Cell Biol. 13, 767–779 (2012).

    Article  CAS  PubMed  Google Scholar 

  187. Nusse, R. Wnt signaling and stem cell control. Cell Res. 18, 523–527 (2008).

    Article  CAS  PubMed  Google Scholar 

  188. Mikels, A., Minami, Y. & Nusse, R. Ror2 receptor requires tyrosine kinase activity to mediate Wnt5A signaling. J. Biol. Chem. 284, 30167–30176 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Florian, M. C. et al. A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing. Nature 503, 392–396 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Naito, A. T. et al. Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes. Cell 149, 1298–1313 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Sumida, T. et al. Complement C1q-induced activation of beta-catenin signalling causes hypertensive arterial remodelling. Nat. Commun. 6, 6241 (2015).

    Article  CAS  PubMed  Google Scholar 

  192. Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 14, 576–590 (2018).

    Article  CAS  PubMed  Google Scholar 

  193. Wilck, N. et al. Salt-responsive gut commensal modulates TH17 axis and disease. Nature 551, 585–589 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Park, S. Y., Kang, M. J. & Han, J. S. Interleukin-1 beta promotes neuronal differentiation through the Wnt5a/RhoA/JNK pathway in cortical neural precursor cells. Mol. Brain 11, 39 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Laffer, C. L., Scott, R. C. 3rd, Titze, J. M., Luft, F. C. & Elijovich, F. Hemodynamics and salt-and-water balance link sodium storage and vascular dysfunction in salt-sensitive subjects. Hypertension 68, 195–203 (2016).

    Article  CAS  PubMed  Google Scholar 

  196. Ando, K. et al. Effect of aging on salt sensitivity of blood pressure in patients with essential hypertension. Clin. Exp. Nephrol. 1, 18–22 (1999).

    Article  Google Scholar 

  197. Kopp, C. et al. 23Na magnetic resonance imaging-determined tissue sodium in healthy subjects and hypertensive patients. Hypertension 61, 635–640 (2013).

    Article  CAS  PubMed  Google Scholar 

  198. Machnik, A. et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat. Med. 15, 545–552 (2009).

    Article  CAS  PubMed  Google Scholar 

  199. Shao, Y. et al. Biological functions of macrophage-derived Wnt5a, and its roles in human diseases. Oncotarget 7, 67674–67684 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Fuster, J. J. et al. Noncanonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion. Diabetes 64, 1235–1248 (2015).

    Article  CAS  PubMed  Google Scholar 

  201. Akoumianakis, I. et al. Adipose tissue-derived WNT5A regulates vascular redox signaling obesity via USP17/RAC1-mediated activation of NADPH oxidases. Sci. Transl Med. 11, eaav5055 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Urakawa, I. et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 444, 770–774 (2006).

    Article  CAS  PubMed  Google Scholar 

  203. Dalton, G. et al. Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling. Proc. Natl Acad. Sci. USA 114, 752–757 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Fakhar, M., Najumuddin, Gul, M. & Rashid, S. Antagonistic role of Klotho-derived peptides dynamics in the pancreatic cancer treatment through obstructing WNT-1 and Frizzled binding. Biophys. Chem. 240, 107–117 (2018).

    Article  CAS  PubMed  Google Scholar 

  205. Chu, Y. et al. Glutathione peroxidase-1 overexpression reduces oxidative stress, and improves pathology and proteome remodeling in the kidneys of old mice. Aging Cell 19, e13154 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Carracedo, J. et al. Klotho modulates the stress response in human senescent endothelial cells. Mech. Ageing Dev. 133, 647–654 (2012).

    Article  CAS  PubMed  Google Scholar 

  207. Jiang, W. et al. Klotho inhibits PKCα/p66SHC-mediated podocyte injury in diabetic nephropathy. Mol. Cell. Endocrinol. 494, 110490 (2019).

    Article  CAS  PubMed  Google Scholar 

  208. Funato, Y., Michiue, T., Asashima, M. & Miki, H. The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-beta-catenin signalling through Dishevelled. Nat. Cell Biol. 8, 501–508 (2006).

    Article  CAS  PubMed  Google Scholar 

  209. Camacho Londoño, J. E. et al. Angiotensin-II-Evoked Ca2+ entry in murine cardiac fibroblasts does not depend on TRPC channels. Cells 9, 322 (2020).

    Article  PubMed Central  CAS  Google Scholar 

  210. Guilluy, C. et al. The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure. Nat. Med. 16, 183–190 (2010).

    Article  CAS  PubMed  Google Scholar 

  211. Sen, P., Shah, P. P., Nativio, R. & Berger, S. L. Epigenetic mechanisms of longevity and aging. Cell 166, 822–839 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Liang, M. Epigenetic mechanisms and hypertension. Hypertension 72, 1244–1254 (2018).

    Article  CAS  PubMed  Google Scholar 

  213. Shchukina, I. et al. Enhanced epigenetic profiling of classical human monocytes reveals a specific signature of healthy aging in the DNA methylome. Nat. Aging 1, 124–141 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Chen, K. & Sun, Z. Activation of DNA demethylases attenuates aging-associated arterial stiffening and hypertension. Aging Cell 17, e12762 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  215. Sahu, A. et al. Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration. Nat. Commun. 9, 4859 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Han, K. et al. Sarcopenia as a determinant of blood pressure in older Koreans: findings from the Korea National Health and Nutrition Examination Surveys (KNHANES) 2008-2010. PLoS ONE 9, e86902 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  217. Nzietchueng, R. et al. Klotho KL-VS genotype is involved in blood pressure regulation. Clin. Chim. Acta 412, 1773–1777 (2011).

    Article  CAS  PubMed  Google Scholar 

  218. Semba, R. D. et al. Klotho in the cerebrospinal fluid of adults with and without Alzheimer’s disease. Neurosci. Lett. 558, 37–40 (2014).

    Article  CAS  PubMed  Google Scholar 

  219. Almeida, O. P. et al. Longevity Klotho gene polymorphism and the risk of dementia in older men. Maturitas 101, 1–5 (2017).

    Article  CAS  PubMed  Google Scholar 

  220. Ninomiya, T. et al. Midlife and late-life blood pressure and dementia in Japanese elderly. Hypertension 58, 22–28 (2011).

    Article  CAS  PubMed  Google Scholar 

  221. Morimoto, A. et al. Sodium sensitivity and cardiovascular events in patients with essential hypertension. Lancet 350, 1734–1737 (1997).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This review article is based on T.F.’s 2019 ASN Homer W. Smith Award lecture, ASN Kidney Week, Washington DC, USA. T.F. acknowledges the excellent support and contributions of K. Ando, T. Shimosawa, M. Nagase, M. Isshiki, T. Marumo, S. Oba, R. Mizuno, Y. Shibagaki, M. Fujita, F. Kawakami-Mori, S. Shibata, H. Kawarazaki, S. Mu, W. Kawarazaki, M. Nishimoto, N. Ayuzawa, D. Hirohama and K. Ueda to his research into salt-sensitive hypertension. The authors’ research was supported by JSPS KAKENHI (Grant nos 15H05788, 18K08028 and 20K21596). The authors are members of the Division of Clinical Epigenetics, University of Tokyo, which is supported by an unrestricted grant from EA Pharma, MSD K.K., Asahi Group Holdings, Astellas Pharma, Omron Healthcare, Shionogi, Mochida Pharmaceutical, Chugai Pharmaceutical, Mitsubishi Tanabe Pharma, Toray Industries, Nippon Boehringer Ingelheim, Fukuda Denshi, Kyowa Kirin, Novartis Pharma, Pfizer and Takeda Pharmaceutical.

Author information

Authors and Affiliations

  1. Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

    Wakako Kawarazaki & Toshiro Fujita

  2. School of Medicine, Shinshu University, Matsumoto, Japan

    Toshiro Fujita

  3. Research Center for Social Systems, Shinshu University, Matsumoto, Japan

    Toshiro Fujita

Authors
  1. Wakako Kawarazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshiro Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.K. and T.F. researched the data for the article; discussed its content; and wrote, reviewed and edited the manuscript.

Corresponding author

Correspondence to Toshiro Fujita.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Nephrology thanks Thu Lee, who co-reviewed with Joseph Gigliotti, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Air-jet stress

An air jet is an environmental stimulus that induces a stress reaction in rats, including increased renal sympathetic nerve activity and decreased urinary sodium excretion.

Hyperphagia

An abnormally strong sensation of hunger or desire to eat, often leading to or accompanied by overeating. Hyperphagia does not subside after eating and often leads to the intake of excessive quantities of food.

Optogenetic stimulation

Optogenetics is a technology that enables optical modulation of cells that have been genetically engineered to express proteins that contain a photoreceptive domain coupled to biological function. Optogenetic stimulation of specific neuron populations enables them to be activated or inhibited using light.

L-type calcium channels

These channels have long been considered the primary route of Ca2+ entry into vascular smooth muscle cells (VSMCs). Ca2+ influx through L-type calcium channels is the principal mediator of the myogenic response, which is the intrinsic ability of VSMCs to contract and relax in response to changes in intraluminal pressure.

Sarcopenia

A common condition among older adults that is characterized by age-dependent loss of muscle mass and function. Sarcopenia is associated with several adverse health outcomes, including frailty.

Vascular dementia

A common type of dementia that is caused by reduced blood flow to the brain.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kawarazaki, W., Fujita, T. Kidney and epigenetic mechanisms of salt-sensitive hypertension. Nat Rev Nephrol 17, 350–363 (2021). https://doi.org/10.1038/s41581-021-00399-2

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-021-00399-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing