Skip to main content

Advertisement

SpringerLink
Log in

Role of Female Sex Hormones and Immune Response in Salt-Sensitive Hypertension Development: Evidence from Experimental Models

  • Mechanisms of Hypertension and Target-Organ Damage (JE Hall and ME Hall, Section Editors)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Purposeof Review

Female sex hormones have systemic effects unrelated to their reproductive function. We describe experiences of different research groups and our own, on aspects related to the importance of female sex hormones on blood pressure (BP) regulation and salt-sensitivity-mediated BP response and salt sensitivity without alterations in BP, as well as renal sodium handling and interactions with the immune system.

Recent Findings

Changes in sodium intake in normotensive premenopausal women cause more BP variations than in men. After menopause, women often develop arterial hypertension (HT) with a profile of sodium sensitivity. Besides, experimental results have shown that in adult rat models resembling the postmenopausal hormonal state induced by ovariectomy, controlling BP is not enough to avoid renal and other tissue infiltration with immune cells, which does not occur when sodium intake is low or normal. Therefore, excess sodium promotes an inflammatory state with the involvement of immune cells. The evidence of activation of adaptive immunity, besides changes in T cell subpopulations, includes changes in sodium transporters and receptors.

Summary

More studies are needed to evaluate the particular sodium sensitivity of women and its meaning. Changes in lifestyle and sodium intake reduction are the main therapeutic steps. However, to face the actual burden of salt-sensitive HT in postmenopausal women and its associated inflammatory/immune changes, it seems reasonable to work on immune cell activity by considering the peripheral blood mononuclear cell phenotypes of molecules and transport proteins related to sodium handle, both to screen for and treat cell activation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

Ang II:

Angiotensin II

BP:

Blood pressure

CV:

Cardiovascular

CYP4A:

Cytochrome P-4504A

D1DR:

D1-like dopamine receptors

DOCA:

Deoxycorticosterone acetate

ECFV:

Extracellular fluid volume

ENaC:

Epithelial sodium channel

ER:

Estrogen receptors

GAGs:

Glycosaminoglycans

GPER-1:

Membrane receptor G protein-coupled estrogen receptor 1

HDZ:

Hydralazine

20-HETE:

20-hydroxyeicosatetraenoic acid

HS:

High sodium

HT:

Arterial hypertension

IF rats:

Intact female rats

NCC:

Neutral sodium chloride cotransporter

NK:

Natural killer

NKA:

Na+, K+-ATPase pump

NKCC1:

Type 1 Na+–K+–2Cl− cotransporter

NKCC2:

Type 2 Na+–K+–2Cl− cotransporter

NS:

Normal salt or normal sodium

oVx:

Ovariectomized

oVx HS:

Ovariectomized hypersodic

oVx NS:

Ovariectomized normosodic

PKC:

Protein kinase C

PBMC:

Peripheral blood mononuclear cells

sgkl gene:

Serum- and glucocorticoid-induced kinase 1 gene

SGK1:

Serum- and glucocorticoid-induced kinase 1

SHR:

Spontaneously hypertensive rats

SSHT:

Salt-sensitive hypertension

Th:

T helper lymphocyte

Tregs:

Regulatory T lymphocytes

VEGF-C:

Vascular endothelial growth factor C

WNK 1:

Lysine-deficient protein kinase 1 [with no lysine (K)]

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. • Barris CT, Faulkner JL, Belin de Chantemèle EJ. Salt sensitivity of blood pressure in women. Hypertension. 2023 (2):268–278. This review highlights the phenomenon of salt sensitivity and blood pressure in women introducing new perspectives.

  2. Faulkner JL, Belin de Chantemèle EJ. Female sex, a major risk factor for salt-sensitive hypertension. Curr Hypertens Rep. 2020;22(12):99.

  3. • Ghazi L, Annabathula RV, Bello NA, Zhou L, Stacey RB, Upadhya B. Hypertension across a woman’s life cycle. Curr Hypertens Rep. 2022;24(12):723–733. This review describes and analyzes the behavior of blood pressure in women’s life span, and emphasizes hypertension and pregnancy.

  4. Sahinoz M, Elijovich F, Ertuglu LA, Ishimwe J, Pitzer A, Saleem M, Mwesigwa N, Kleyman TR, Laffer CL, Kirabo A. Salt sensitivity of blood pressure in blacks and women: a role of inflammation, oxidative stress, and epithelial Na+ channel. Antioxid Redox Signal. 2021;35(18):1477–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. •• WHO, Recommendation. (2020). Available online: https://www.who.int/news-room/fact-sheets/detail/salt-reduction. Available data from hypertension, cardiovascular disease, and metabolic syndrome around the world.

  6. • Appel LJ, Frohlich ED, Hall JE, Pearson TA, Sacco RL, Seals DR, Sacks FM, Smith SC Jr, Vafiadis DK, Van Horn LV. The importance of population-wide sodium reduction as a means to prevent cardiovascular disease and stroke: a call to action from the American Heart Association. Circulation. 2011 15;123(10):1138–43. Recommendations from AHA about the importance to reduce sodium consumption.

  7. Matthews EL, Brian MS, Ramick MG, Lennon-Edwards S, Edwards DG, Farquhar WB. High dietary sodium reduces brachial artery flow-mediated dilation in humans with salt-sensitive and salt-resistant blood pressure. J Appl Physiol (1985). 2015 15;118(12):1510–5.

  8. • Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M. Salt sensitivity, pulse pressure, and death in normal and hypertensive humans. Hypertension. 2001;37(2 Pt 2):429–32. Importance of salt sensitivity beyond hypertension.

  9. de Wardener HE, MacGregor GA. Harmful effects of dietary salt in addition to hypertension. J Hum Hypertens. 2002;16(4):213–23.

    Article  PubMed  Google Scholar 

  10. •• Rossitto G, Delles C. Does excess tissue sodium storage regulate blood pressure? Curr Hypertens Rep. 2022;24(5):115–122. Revision and discussion about the new role proposed for space in the skin to buffer excess sodium intake.

  11. • Elijovich F, Weinberger MH, Anderson CA, Appel LJ, Bursztyn M, Cook NR, Dart RA, Newton-Cheh CH, Sacks FM, Laffer CL. American Heart Association Professional and Public Education Committee of the Council on Hypertension; Council on Functional Genomics and Translational Biology; and Stroke Council. Salt sensitivity of blood pressure: a scientific statement from the American Heart Association. Hypertension. 2016;68(3):e7-e46. New statements from AHA about the importance of salt sensitivity and hypertension.

  12. Azurmendi PJ, Toro AR, Celía AF, Guevara D, Solerno MR, Di Ciano LA, Toledo JE, Ibarra FR, Arrizurieta EE, Oddo EM. Behavior of the renal kallikrein in spontaneously hypertensive rats: influence of sexual hormones and aldosterone-sensitive distal nephron ion channels. Peptides. 2023;160:170925.

    Article  CAS  PubMed  Google Scholar 

  13. Reckelhoff JF. Gender differences in the regulation of blood pressure. Hypertension. 2001;37(5):1199–208.

    Article  CAS  PubMed  Google Scholar 

  14. • Maranon R, Reckelhoff JF. Sex and gender differences in control of blood pressure. Clin Sci (Lond). 2013;125(7):311–8. Revision of epidemiological and experimental evidence on gender differences in blood pressure regulation.

  15. Ji H, Niiranen TJ, Rader F, Henglin M, Kim A, Ebinger JE, Claggett B, Merz CNB, Cheng S. Sex differences in blood pressure associations with cardiovascular outcomes. Circulation. 2021;143(7):761–3.

    Article  PubMed  PubMed Central  Google Scholar 

  16. • Munger K, Baylis C. Sex differences in renal hemodynamics in rats. Am J Physiol. 1988;254(2 Pt 2):F223–31. This paper reports one of the first experimental observations about sex differences between renal hemodynamics and blood pressure in rats.

  17. • Veiras LC, Girardi ACC, Curry J, Pei L, Ralph DL, Tran A, Castelo-Branco RC, Pastor-Soler N, Arranz CT, Yu ASL, McDonough AA. Sexual dimorphic pattern of renal transporters and electrolyte homeostasis. J Am Soc Nephrol. 2017;28(12):3504–17. This paper describes experimental findings about sexual differences in nephron sodium transporters in rats.

  18. Di Ciano LA, Azurmendi PJ, Vlachovsky SG, Celía AF, Oddo, EM, Arrizurieta EE, Silberstein CM, Ibarra FR. Diferencias de género en presión arterial, función renal y respuesta a la dieta hipersódica en ratas Wistar. Revista de Nefrología Diálisis y Trasplante. 2018;38(1):15–27. Available from https://www.revistarenal.org.ar/index.php/rndt/article/view/294.

  19. •• Pechere-Bertschi A, Burnier M. Gonadal steroids, salt-sensitivity and renal function. Curr Opin Nephrol Hypertens. 2007;16(1):16–21. One of the most authoritative and cited reviews about sex hormones, renal physiology, and blood pressure in women.

  20. Boddu R, Fan C, Rangarajan S, Sunil B, Bolisetty S, Curtis LM. Unique sex- and age-dependent effects in protective pathways in acute kidney injury. Am J Physiol Renal Physiol. 2017;313(3):F740–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Akahoshi M, Soda M, Nakashima E, Shimaoka K, Seto S, Yano K. Effects of menopause on trends of serum cholesterol, blood pressure, and body mass index. Circulation. 1996;94(1):61–6.

    Article  CAS  PubMed  Google Scholar 

  22. • Kim JM, Kim TH, Lee HH, Lee SH, Wang T. Postmenopausal hypertension and sodium sensitivity. J Menopausal Med. 2014;20(1):1–6. This review focuses on female sex hormones decline and salt-sensitive hypertension development.

  23. •• Cobo G, Hecking M, Port FK, Exner I, Lindholm B, Stenvinkel P, Carrero JJ. Sex and gender differences in chronic kidney disease: progression to end-stage renal disease and haemodialysis. Clin Sci (Lond). 2016;130(14):1147–63. This work describes epidemiological findings about sex differences in renal disease progression. A call of attention to the concept of female hormone protection.

  24. • Toering TJ, Gant CM, Visser FW, van der Graaf AM, Laverman GD, Danser AHJ, Faas MM, Navis G, Lely AT. Sex differences in renin-angiotensin-aldosterone system affect extracellular volume in healthy subjects. Am J Physiol Renal Physiol. 2018;314(5):F873-F78. This paper analyzes women’s and men’s extracellular volume regulation upon changes in sodium intake.

  25. •• He J, Gu D, Chen J, Jaquish CE, Rao DC, Hixson JE, Chen JC, Duan X, Huang JF, Chen CS, Kelly TN, Bazzano LA, Whelton PK; GenSalt Collaborative Research Group. Gender difference in blood pressure responses to dietary sodium intervention in the GenSalt study. J Hypertens. 2009;27(1):48–54. Observational-interventional study that analyzes gender differences in the behavior of blood pressure and salt sensitivity to changes in sodium intake in a great number of experimental individuals.

  26. Wynne FL, Payne JA, Cain AE, Reckelhoff JF, Khalil RA. Age-related reduction in estrogen receptor-mediated mechanisms of vascular relaxation in female spontaneously hypertensive rats. Hypertension. 2004;43(2):405–12. https://doi.org/10.1161/01.HYP.0000111833.82664.0c.

    Article  CAS  PubMed  Google Scholar 

  27. • Vlachovsky SG, Di Ciano LA, Oddo EM, Azurmendi PJ, Goette NP, Arrizurieta EE, Silberstein C, Ibarra FR. Ovariectomy and high salt increase blood pressure and alter sodium transport proteins in peripheral blood mononuclear cells of adult Wistar rats. Exp Physiol. 2021;106(10):2107–2123. https://doi.org/10.1113/EP089553. This experimental work shows the simultaneous activation of peripheral immune cells and kidney infiltration in ovariectomized Wistar rats that develop salt-sensitive hypertension.

  28. Szmuilowicz ED, Adler GK, Williams JS, Green DE, Yao TM, Hopkins PN, Seely EW. Relationship between aldosterone and progesterone in the human menstrual cycle. J Clin Endocrinol Metab. 2006;91(10):3981–7. https://doi.org/10.1210/jc.2006-1154.

    Article  CAS  PubMed  Google Scholar 

  29. Rojas-Vega L, Gamba G. Mini-review: regulation of the renal NaCl cotransporter by hormones. Am J Physiol Renal Physiol. 2016;310(1):F10–4. https://doi.org/10.1152/ajprenal.00354.2015.

    Article  CAS  PubMed  Google Scholar 

  30. •• Titze J, Luft FC, Bauer K, Dietsch P, Lang R, Veelken R, Wagner H, Eckardt KU, Hilgers KF. Extrarenal Na+ balance, volume, and blood pressure homeostasis in intact and ovariectomized deoxycorticosterone-acetate salt rats. Hypertension. 2006;47:1101–7  https://doi.org/10.1161/01.HYP.0000221039.17735.1a. This paper shows findings about a third compartment to buffer body sodium.

  31. Lara LS, McCormack M, Semprum-Prieto LC, Shenouda S, Majid DS, Kobori H, Navar LG, Prieto MC. AT1 receptor-mediated augmentation of angiotensinogen, oxidative stress, and inflammation in ANG II-salt hypertension. Am J Physiol Renal Physiol. 2012;302(1):F85-94. https://doi.org/10.1152/ajprenal.00351.2011.

    Article  CAS  PubMed  Google Scholar 

  32. • Reckelhoff JF, Fortepiani LA. Novel mechanisms responsible for postmenopausal hypertension. Hypertension. 2004;43(5):918–23. https://doi.org/10.1161/01.HYP.0000124670.03674.15. This review discussed possible mechanisms that could play a role in postmenopausal hypertension and proposed the aging female spontaneously hypertensive rat as a postmenopausal women model.

  33. • Felder RA, Gildea JJ, Xu P, Yue W, Armando I, Carey RM, Jose PA. Inverse salt sensitivity of blood pressure: mechanisms and potential relevance for prevention of cardiovascular disease. Curr Hypertens Rep. 2022;24(9):361–74. https://doi.org/10.1007/s11906-022-01201-9. This review describes another face ofsodium regulation: when salt intake is low.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Banday AA, Lokhandwala MF.Renal dopamine oxidation and inflammation in high salt fed rats. J Am Heart Assoc. 2020;9(1):e014977. doi: https://doi.org/10.1161/JAHA.119.014977.

  35. Brismar H, Holtbäck U, Aperia A. Mechanisms by which intrarenal dopamine and ANP interact to regulate sodium metabolism. Clin Exp Hypertens. 2000;22(3):303–7.

    Article  CAS  PubMed  Google Scholar 

  36. Azurmendi PJ, Oddo EM, Obika LF, Corbera NL, Martín RS, Ibarra FR, Arrizurieta EE. Gonadectomy influences blood pressure through the kallikrein-kinin system. Kidney Blood Press Res. 2009;32(5):342–8.

    Article  CAS  PubMed  Google Scholar 

  37. • Di Ciano LA, Azurmendi PJ, Toledo JE, Oddo EM, Zotta E, Ochoa F, Arrizurieta EE, Ibarra FR. Ovariectomy causes overexpression of renal Na(+), K(+)-ATPase and sodium-sensitive hypertension in adult Wistar rats. Clin Exp Hypertens. 2013;35(7):475–83. https://doi.org/10.3109/10641963.2012.758273. This research shows a first description about a salt-sensitive hypertension experimental model developed in ovariectomized adult Wistar rats.

  38. Campese VM, Karubian F, Bigazzi R. Hemodynamic alterations and urinary albumin excretion in patients with essential hypertension. Am J Kidney Dis. 1993;21(5 Suppl 2):15–21.

    Article  CAS  PubMed  Google Scholar 

  39. • Li D, Cheng SX, Fisone G, Caplan MJ, Ohtomo Y, Aperia A. Effects of okadaic acid, calyculin A, and PDBu on state of phosphorylation of rat renal Na+-K+-ATPase. Am J Physiol. 1998;275(6):F863–9. This research shows the posttranslational regulation of renal sodium pump by phosphorylation/dephosphorylation.

  40. Ibarra FR, Cheng SX, Agrén M, Svensson LB, Aizman O, Aperia A. Intracellular sodium modulates the state of protein kinase C phosphorylation of rat proximal tubule Na+, K+-ATPase. Acta Physiol Scand. 2002;175(2):165–71.

    Article  CAS  PubMed  Google Scholar 

  41. • Di Ciano LA, Azurmendi PJ, Colombero C, Levin G, Oddo EM, Arrizurieta EE, Nowicki S, Ibarra FR. Defective renal dopamine function and sodium-sensitive hypertension in adult ovariectomized Wistar rats: role of the cytochrome P-450 pathway. Am J Physiol Renal Physiol. 2015;308(12):F1358–68. This research demonstrated the defective phosphorylation of the renal sodium pump in the ovariectomized salt-sensitive Wistar rats experimental model.

  42. Sandberg K, Ji H, Einstein G, Au A, Hay M. Is immune system-related hypertension associated with ovarian hormone deficiency? Exp Physiol. 2016;101(3):368–74.

    Article  CAS  PubMed  Google Scholar 

  43. •• Rosenzweig R, Gupta S, Kumar V, Gumina RJ, Bansal SS. Estrogenic bias in T-lymphocyte biology: implications for cardiovascular disease. Pharmacol Res. 2021;170:105606. This review overviews the estrogen effects on T–cell regulation and cardiovascular disease.

  44. Phiel KL, Henderson RA, Adelman SJ, Elloso MM. Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations. Immunol Lett. 2005;97(1):107–13.

    Article  CAS  PubMed  Google Scholar 

  45. Grossman CJ, Roselle GA. The interrelationship of the HPG-thymic axis and immune system regulation. J Steroid Biochem. 1983;19(1B):461–7.

    Article  CAS  PubMed  Google Scholar 

  46. • Jacobsen H, Klein SL. Sex differences in immunity to viral infections. Front Immunol. 2021;12:720952. Interesting review which focuses on sex-specific differences in immunity and outcomes during SARS-CoV-2 infection.

  47. Hao S, Zhao J, Zhou J, Zhao S, Hu Y, Hou Y. Modulation of 17beta-estradiol on the number and cytotoxicity of NK cells in vivo related to MCM and activating receptors. Int Immunopharmacol. 2007;7(13):1765–75.

    Article  CAS  PubMed  Google Scholar 

  48. Bengtsson AK, Ryan EJ, Giordano D, Magaletti DM, Clark EA. 17beta-estradiol (E2) modulates cytokine and chemokine expression in human monocyte-derived dendritic cells. Blood. 2004;104(5):1404–10.

    Article  CAS  PubMed  Google Scholar 

  49. Knöferl MW, Angele MK, Diodato MD, Schwacha MG, Ayala A, Cioffi WG, Bland KI, Chaudry IH. Female sex hormones regulate macrophage function after trauma-hemorrhage and prevent increased death rate from subsequent sepsis. Ann Surg. 2002;235(1):105–12.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Adachi A, Honda T, Egawa G, Kanameishi S, Takimoto R, Miyake T, Hossain MR, Komine M, Ohtsuki M, Gunzer M, Ikuta K, Kabashima K. Estradiol suppresses psoriatic inflammation in mice by regulating neutrophil and macrophage functions. J Allergy Clin Immunol. 2022;150(4):909-919.e8.

    Article  CAS  PubMed  Google Scholar 

  51. Mateus D, Sebastião AI, Carrascal MA, Carmo AD, Matos AM, Cruz MT. Crosstalk between estrogen, dendritic cells, and SARS-CoV-2 infection. Rev Med Virol. 2022;32(3): e2290.

    Article  CAS  PubMed  Google Scholar 

  52. • Chen RY, Fan YM, Zhang Q, Liu S, Li Q, Ke GL, Li C, You Z. Estradiol inhibits Th17 cell differentiation through inhibition of RORγT transcription by recruiting the ERα/REA complex to estrogen response elements of the RORγT promoter. J Immunol. 2015;194(8):4019–28. This research shows the pathway used by estrogen to inhibit Th17 cell polarization.

  53. •• Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway. J Neurosci Res. 2006;84(2):370–8. This research shows findings related to estrogen modulation of T cell subpopulations and involved pathways.

  54. Straub RH. The complex role of estrogens in inflammation. Endocr Rev. 2007;28:521–74. https://doi.org/10.1210/er.2007-0001.

    Article  CAS  PubMed  Google Scholar 

  55. Polanczyk MJ, Carson BD, Subramanian S, Afentoulis M, Vandenbark AA, Ziegler SF, Offner H. Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J Immunol. 2004 15;173(4):2227–30.

  56. •• Mattson DL. Immune mechanisms of salt-sensitive hypertension and renal end-organ damage. Nat Rev Nephrol. 2019;15(5):290–300. Interesting review of the relationship among salt sensitivity, immune mechanisms, and hypertension. A hypothesis regarding the onset and evolution of those variables is proposed.

  57. Butts CL, Shukair SA, Duncan KM, Bowers E, Horn C, Belyavskaya E, et al. Progesterone inhibits mature rat dendritic cells in a receptor-mediated fashion. Int Immunol. 2007;19:287–96.

    Article  CAS  PubMed  Google Scholar 

  58. Lee JH, Ulrich B, Cho J, Park J, Kim CH. Progesterone promotes differentiation of human cord blood fetal T cells into T regulatory cells but suppresses their differentiation into Th17 cells. J Immunol. 2011;187:1778–87.

    Article  CAS  PubMed  Google Scholar 

  59. •• Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, Goronzy J, Weyand C, Harrison DG. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J Exp Med. 2007;204(10):2449–60. First work describing the importance of immunity in arterial hypertension in male mice.

  60. Norlander AE, Madhur MS, Harrison DG. The immunology of hypertension. J Exp Med. 2018;215(1):21–33. Erratum in: J Exp Med. 2018

  61. •• Pai AV, Maddox T, Sandberg K. T Cells and hypertension: solved and unsolved mysteries regarding the female rat. Physiology (Bethesda). 2018;33(4):254–260. This review analyzes the role of T cells in female rats as hypertension promoters.

  62. Xiao L, Kirabo A, Wu J, Saleh MA, Zhu L, Wang F, Takahashi T, Loperena R, Foss JD, Mernaugh RL, Chen W, Roberts J 2nd, Osborn JW, Itani HA, Harrison DG. Renal denervation prevents immune cell activation and renal inflammation in angiotensin ii-induced hypertension. Circ Res. 2015;117(6):547–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mikolajczyk TP, Nosalski R, Szczepaniak P, Budzyn K, Osmenda G, Skiba D, Sagan A, Wu J, Vinh A, Marvar PJ, Guzik B, Podolec J, Drummond G, Lob HE, Harrison DG, Guzik TJ. Role of chemokine RANTES in the regulation of perivascular inflammation, T-cell accumulation, and vascular dysfunction in hypertension. FASEB J. 2016;30(5):1987–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. •• Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, Park JK, Beck FX, Müller DN, Derer W, Goss J, Ziomber A, Dietsch P, Wagner H, van Rooijen N, Kurtz A, Hilgers KF, Alitalo K, Eckardt KU, Luft FC, Kerjaschki D, Titze J. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med. 2009;15(5):545–52. This research paper describes different strategies to demonstrate the role of interstitial and macrophages to regulate salt balance. The work proposes a hypertonic sodium accumulation in the skin of male rats and mice.

  65. • Ren J, Crowley SD. Role of T-cell activation in salt-sensitive hypertension. Am J Physiol Heart Circ Physiol. 2019;316(6):H1345-H1353. Interesting review with clear concepts concerning T cells, sodium, and hypertension.

  66. Pernis AB. Estrogen and CD4+ T cells. Curr Opin Rheumatol. 2007;19(5):414–20.

    Article  CAS  PubMed  Google Scholar 

  67. Mirandola L, Wade R, Verma R, Pena C, Hosiriluck N, Figueroa JA, Cobos E, Jenkins MR, Chiriva-Internati M. Sex-driven differences in immunological responses: challenges and opportunities for the immunotherapies of the third millennium. Int Rev Immunol. 2015;34(2):134–42.

    Article  CAS  PubMed  Google Scholar 

  68. Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496(7446):518–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. •• Norlander AE, Saleh MA, Pandey AK, Itani HA, Wu J, Xiao L, Kang J, Dale BL, Goleva SB, Laroumanie F, Du L, Harrison DG, Madhur MS. A salt-sensing kinase in T lymphocytes, SGK1, drives hypertension and hypertensive end-organ damage. JCI Insight. 2017;2(13):e92801. This research demonstrated the phenotypic changes in T lymphocytes in mice exposed to high sodium levels associated with hypertension.

  70. Karitskaya I, Aksenov N, Vassilieva I, Zenin V, Marakhova I. Long-term regulation of Na, K-ATPase pump during T-cell proliferation. Pflugers Arch. 2010;460(4):777–89.

    Article  CAS  PubMed  Google Scholar 

  71. •• Vereninov AA, Vassilieva IO, Yurinskaya VE, Matveev VV, Glushankova LN, Lang F, Matskevitch JA. Differential transcription of ion transporters, NHE1, ATP1B1, NKCC1 in human peripheral blood lymphocytes activated to proliferation. Cell Physiol Biochem. 2001;11(1):19–26. This article shows part of the machinery that human lymphocytes use to activate their proliferation.

  72. Köchl R, Thelen F, Vanes L, Brazão TF, Fountain K, Xie J, Huang CL, Lyck R, Stein JV, Tybulewicz VL. WNK1 kinase balances T cell adhesion versus migration in vivo. Nat Immunol. 2016;17(9):1075–83. Erratum in: Nat Immunol. 2017;18(2):246.

  73. Lang F, Artunc F, Vallon V. The physiological impact of the serum and glucocorticoid-inducible kinase SGK1. Curr Opin Nephrol Hypertens. 2009;18(5):439–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Buttarelli FR, Fanciulli A, Pellicano C, Pontieri FE. The dopaminergic system in peripheral blood lymphocytes: from physiology to pharmacology and potential applications to neuropsychiatric disorders. Curr Neuropharmacol. 2011;9(2):278–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Barbaro NR, Foss JD, Kryshtal DO, Tsyba N, Kumaresan S, Xiao L, Mernaugh RL, Itani HA, Loperena R, Chen W, Dikalov S, Titze JM, Knollmann BC, Harrison DG, Kirabo A. Dendritic cell amiloride-sensitive channels mediate sodium-induced inflammation and hypertension. Cell Rep. 2017;21(4):1009–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fehrenbach DJ, Mattson DL. Inflammatory macrophages in the kidney contribute to salt-sensitive hypertension. Am J Physiol Renal Physiol. 2020;318(3):F544–8. https://doi.org/10.1152/ajprenal.00454.2019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rudemiller N, Lund H, Jacob HJ, Geurts AM, Mattson DL. PhysGen Knockout Program. CD247 modulates blood pressure by altering T-lymphocyte infiltration in the kidney. Hypertension. 2014;63(3):559–64.

  78. Evans LC, Petrova G, Kurth T, Yang C, Bukowy JD, Mattson DL, Cowley AW Jr. Increased perfusion pressure drives renal T-cell infiltration in the Dahl salt-sensitive rat. Hypertension. 2017;70(3):543–51.

    Article  CAS  PubMed  Google Scholar 

  79. Pai AV, West CA, de Souza AMA, Kadam PS, Pollner EJ, West DA Jr, Li J, Ji H, Wu X, Zhu MJ, Baylis C, Sandberg K. Renal T cell infiltration occurs despite attenuation of development of hypertension with hydralazine in Envigo’s female Dahl rat maintained on a low-Na+ diet. Am J Physiol Renal Physiol. 2019;317(3):F572–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Vlachovsky SG, Azurmendi PJ, Oddo EM, Di Ciano LA, Rodriguez SR, Goette NP, Paz LA, Silberstein C, Ibarra FR. Immune response after lowering-blood pressure in salt-sensitive hypertension rat model. Joint Meeting SAIC SAI&FAIC SAFIS 2022. Abstract published in: Medicina, Buenos Aires. 2022;82 (Suppl V):208.URL: https://medicinabuenosaires.com/revistas/vol82-22/s5/1s5.pdf.

  81. Lenda DM, Boegehold MA. Effect of a high-salt diet on oxidant enzyme activity in skeletal muscle microcirculation. Am J Physiol Heart Circ Physiol. 2002;282(2):H395-402.

    Article  CAS  PubMed  Google Scholar 

  82. Guers JJ, Kasecky-Lardner L, Farquhar WB, Edwards DG, Lennon SL. Voluntary wheel running prevents salt-induced endothelial dysfunction: role of oxidative stress. J Appl Physiol (1985). 2019 1;126(2):502–510.

  83. Greaney JL, DuPont JJ, Lennon-Edwards SL, Sanders PW, Edwards DG, Farquhar WB. Dietary sodium loading impairs microvascular function independent of blood pressure in humans: role of oxidative stress. J Physiol. 2012;590(21):5519–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Eisenach JH, Gullixson LR, Kost SL, Joyner MJ, Turner ST, Nicholson WT. Sex differences in salt sensitivity to nitric oxide dependent vasodilation in healthy young adults. J Appl Physiol (1985). 2012;112(6):1049–53.

  85. Scuteri A, Stuehlinger MC, Cooke JP, Wright JG, Lakatta EG, Anderson DE, Fleg JL. Nitric oxide inhibition as a mechanism for blood pressure increase during salt loading in normotensive postmenopausal women. J Hypertens. 2003;21(7):1339–46.

    Article  CAS  PubMed  Google Scholar 

  86. Costa-Fraga FP, Goncalves GK, Souza-Neto FP, Reis AM, Capettini LA, Santos RA, Fraga-Silva RA, Stergiopulos N, da Silva RF. Age-related changes in vascular responses to angiotensin-(1–7) in female mice. J Renin Angiotensin Aldosterone Syst. 2018;19(3):1470320318789332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Harrison-Bernard LM, Schulman IH, Raij L. Postovariectomy hypertension is linked to increased renal AT1 receptor and salt sensitivity. Hypertension. 2003;42(6):1157–63.

    Article  CAS  PubMed  Google Scholar 

  88. Meyer MR, Haas E, Barton M. Gender differences of cardiovascular disease: new perspectives for estrogen receptor signaling. Hypertension. 2006;47(6):1019–26.

    Article  CAS  PubMed  Google Scholar 

  89. Ylikorkala O, Orpana A, Puolakka J, Pyörälä T, Viinikka L. Postmenopausal hormonal replacement decreases plasma levels of endothelin-1. J Clin Endocrinol Metab. 1995;80(11):3384–7.

    CAS  PubMed  Google Scholar 

  90. Komesaroff PA, Esler MD, Sudhir K. Estrogen supplementation attenuates glucocorticoid and catecholamine responses to mental stress in perimenopausal women. J Clin Endocrinol Metab. 1999;84(2):606–10.

    CAS  PubMed  Google Scholar 

  91. SenthilKumar G, Katunaric B, Bordas-Murphy H, Young M, Doren EL, Schulz ME, Widlansky ME, Freed JK. 17β-Estradiol promotes sex-specific dysfunction in isolated human arterioles. Am J Physiol Heart Circ Physiol. 2023;324(3):H330–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ji H, Kim A, Ebinger JE, Niiranen TJ, Claggett BL, Bairey Merz CN, Cheng S. Sex differences in blood pressure trajectories over the life course. JAMA Cardiol. 2020;5(3):19–26.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Jobin K, Müller DN, Jantsch J, Kurts C. Sodium and its manifold impact on our immune system. Trends Immunol. 2021;42(6):469–79.

    Article  CAS  PubMed  Google Scholar 

  94. •• Bie P. Mechanisms of sodium balance: total body sodium, surrogate variables, and renal sodium excretion. Am J Physiol Regul Integr Comp Physiol. 2018;315(5):R945-R962. This outstanding analytical review about body sodium balance revises and explains classic and recent findings.

  95. • Jhee JH, Park HC, Choi HY. Skin sodium and blood pressure regulation. Electrolyte Blood Press. 2022;20(1):1–9. This review debates the question of whether skin sodium accumulation is “good or evil.” The potential double edge sword of skin-high sodium.

  96. Mobasheri A. Correlation between [Na+], [glycosaminoglycan] and Na+/K+ pump density in the extracellular matrix of bovine articular cartilage. Physiol Res. 1998;47(1):47–52.

    CAS  PubMed  Google Scholar 

  97. •• Wiig H, Luft FC, Titze JM. The interstitium conducts extrarenal storage of sodium and represents a third compartment essential for extracellular volume and blood pressure homeostasis. Acta Physiol (Oxf). 2018;222(3). This review describes the findings that support the theory about the interstitium as a third sodium compartment and analyzes many many excellent works performed by this research group.

  98. Schmidlin O, Sebastian AF, Morris RC Jr. What initiates the pressor effect of salt in salt-sensitive humans? Observations in normotensive blacks Hypertension. 2007;49(5):1032–9.

    CAS  PubMed  Google Scholar 

  99. Laffer CL, Scott RC 3rd, Titze JM, Luft FC, Elijovich F. Hemodynamics and salt-and-water balance link sodium storage and vascular dysfunction in salt-sensitive subjects. Hypertension. 2016;68(1):195–203.

    Article  CAS  PubMed  Google Scholar 

  100. Titze J, Krause H, Hecht H, Dietsch P, Rittweger J, Lang R, Kirsch KA, Hilgers KF. Reduced osmotically inactive Na storage capacity and hypertension in the Dahl model. Am J Physiol Renal Physiol. 2002;283(1):F134–41.

    Article  CAS  PubMed  Google Scholar 

  101. Titze J, Shakibaei M, Schafflhuber M, Schulze-Tanzil G, Porst M, Schwind KH, Dietsch P, Hilgers KF. Glycosaminoglycan polymerization may enable osmotically inactive Na+ storage in the skin. Am J Physiol Heart Circ Physiol. 2004;287(1):H203–8.

    Article  CAS  PubMed  Google Scholar 

  102. • Titze J, Lang R, Ilies C, Schwind KH, Kirsch KA, Dietsch P, Luft FC, Hilgers KF. Osmotically inactive skin Na+ storage in rats. Am J Physiol Renal Physiol. 2003;285(6):F1108–17. This article is one of the first original works from the group. Studies were conducted in male, fertile female, and ovariectomized female Sprague Dawley (SD) rats, to demonstrate the sodium storage in the skin.

  103. Rakova N, Jüttner K, Dahlmann A, Schröder A, Linz P, Kopp C, Rauh M, Goller U, Beck L, Agureev A, Vassilieva G, Lenkova L, Johannes B, Wabel P, Moissl U, Vienken J, Gerzer R, Eckardt KU, Müller DN, Kirsch K, Morukov B, Luft FC, Titze J. Long-term space flight simulation reveals infradian rhythmicity in human Na(+) balance. Cell Metab. 2013 8;17(1):125–31.

  104. Dahlmann A, Dörfelt K, Eicher F, Linz P, Kopp C, Mössinger I, Horn S, Büschges-Seraphin B, Wabel P, Hammon M, Cavallaro A, Eckardt KU, Kotanko P, Levin NW, Johannes B, Uder M, Luft FC, Müller DN, Titze JM. Magnetic resonance-determined sodium removal from tissue stores in hemodialysis patients. Kidney Int. 2015;87(2):434–41.

    Article  CAS  PubMed  Google Scholar 

  105. Wiig H, Schröder A, Neuhofer W, Jantsch J, Kopp C, Karlsen TV, Boschmann M, Goss J, Bry M, Rakova N, Dahlmann A, Brenner S, Tenstad O, Nurmi H, Mervaala E, Wagner H, Beck FX, Müller DN, Kerjaschki D, Luft FC, Harrison DG, Alitalo K, Titze J. Immune cells control skin lymphatic electrolyte homeostasis and blood pressure. J Clin Invest. 2013;123(7):2803–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Thowsen IM, Karlsen TV, Nikpey E, Haslene-Hox H, Skogstrand T, Randolph GJ, Zinselmeyer BH, Tenstad O, Wiig H. Na+ is shifted from the extracellular to the intracellular compartment and is not inactivated by glycosaminoglycans during high salt conditions in rats. J Physiol. 2022;600(10):2293–309.

    Article  CAS  PubMed  Google Scholar 

  107. •• Rossitto G, Mary S, Chen JY, Boder P, Chew KS, Neves KB, Alves RL, Montezano AC, Welsh P, Petrie MC, Graham D, Touyz RM, Delles C. Tissue sodium excess is not hypertonic and reflects extracellular volume expansion. Nat Commun. 2020;11(1):4222. This work demonstrated that isotonic sodium accumulates not only in the skin, and debates recent findings regarding skin sodium accumulation. The article shows results in male and female rats, and in women and men.

  108. Trincot CE, Caron KM. Lymphatic function and dysfunction in the context of sex differences. ACS Pharmacol Transl Sci. 2019;2(5):311–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Karlsen TV, Nikpey E, Han J, Reikvam T, Rakova N, Castorena-Gonzalez JA, Davis MJ, Titze JM, Tenstad O, Wiig H. High-salt diet causes expansion of the lymphatic network and increased lymph flow in skin and muscle of rats. Arterioscler Thromb Vasc Biol. 2018;38(9):2054–64.

    Article  CAS  PubMed  Google Scholar 

  110. •• Machnik A, Dahlmann A, Kopp C, Goss J, Wagner H, van Rooijen N, Eckardt KU, Müller DN, Park JK, Luft FC, Kerjaschki D, Titze J. Mononuclear phagocyte system depletion blocks interstitial tonicity-responsive enhancer binding protein/vascular endothelial growth factor C expression and induces salt-sensitive hypertension in rats. Hypertension. 2010;55(3):755–61. This investigation demonstrates that mononuclear phagocyte system depletion in the skin induces hypertension in male rats treated with DOCA and moderate amounts of sodium loading.

  111. Silha JV, Krsek M, Sucharda P, Murphy LJ. Angiogenic factors are elevated in overweight and obese individuals. Int J Obes (Lond). 2005;29(11):1308–14.

    Article  CAS  PubMed  Google Scholar 

  112. Valenzuela GJ, Brace RA, Longo LD. Lymphatic and vascular responses to fluid infusion in castrated and noncastrated sheep. Am J Physiol. 1987;252(6 Pt 2):R1114–8.

    CAS  PubMed  Google Scholar 

  113. •• Selvarajah V, Mäki-Petäjä KM, Pedro L, Bruggraber SFA, Burling K, Goodhart AK, Brown MJ, McEniery CM, Wilkinson IB. Novel mechanism for buffering dietary salt in humans: effects of salt loading on skin sodium, vascular endothelial growth factor C, and blood pressure. Hypertension. 2017;70(5):930–937. This paper describes the behavior of BP in women and men, and its relationship with subcutaneous electrolytes.

  114. • Barnett AM, Babcock MC, Watso JC, Migdal KU, Gutiérrez OM, Farquhar WB, Robinson AT. High dietary salt intake increases urinary NGAL excretion and creatinine clearance in healthy young adults. Am J Physiol Renal Physiol. 2022 Apr 1;322(4):F392-F402. This research shows a crossover design from low to moderately high sodium and demonstrates that sodium increases urinary NGAL and GFR in women and men pooled together.

  115. Madhur MS, Elijovich F, Alexander MR, Pitzer A, Ishimwe J, Van Beusecum JP, Patrick DM, Smart CD, Kleyman TR, Kingery J, Peck RN, Laffer CL, Kirabo A. Hypertension: do inflammation and immunity hold the key to solving this epidemic? Circ Res. 2021;128(7):908–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. •• Mill JG, Baldo MP, Molina MDCB, Schmidt MI, Barreto SM, Chor D, Griep RH, Matos SM, Ribeiro ALP, Duncan BB, Aquino EM, Lotufo PA, Bensenor I. Sex-specific patterns in the association between salt intake and blood pressure: the ELSA-Brasil study. J Clin Hypertens (Greenwich). 2019; 21(4):502–509. Excellent study with a large number of adult participants, women and men. Variables are corrected by sex, age, medication, and blood pressure response to sodium intake. This study shows that women have a higher responsiveness of BP according to salt intake than men.

  117. •• Fehrenbach DJ, Nguyen B, Alexander MR, Madhur MS. Modulating T cell phenotype and function to treat hypertension. Kidney360. 2023;4(4):e534-e543. This review highlights the importance of changes in T cell phenotype as potential targets to treat hypertension.

  118. El Khoudary SR. Age at menopause onset and risk of cardiovascular disease around the world. Maturitas. 2020;141:33–8.

    Article  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Claudia Silberstein and Fernando R. Ibarra contributed equally to this manuscript.

Authors and Affiliations

  1. Universidad de Buenos Aires, Instituto de Investigaciones Medicas A. Lanari, Laboratorio de Nefrología Experimental y Bioquímica Molecular, Combatientes de Malvinas 3150, Buenos Aires, 1427, Argentina

    Sandra G. Vlachovsky, Luis A. Di Ciano, Elisabet M. Oddo, Pablo J. Azurmendi & Fernando R. Ibarra

  2. Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Instituto de Investigaciones Médicas A. Lanari, Buenos Aires, Argentina

    Sandra G. Vlachovsky, Elisabet M. Oddo, Pablo J. Azurmendi & Fernando R. Ibarra

  3. Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Médicas, Departamento de Ciencias Fisiológicas. Instituto de Fisiología y Biofísica B. Houssay (IFIBIO-Houssay), Laboratorio de Fisiología Renal, Paraguay 2155, piso 4, Buenos Aires, 1121, Argentina

    Claudia Silberstein & Fernando R. Ibarra

Authors
  1. Sandra G. Vlachovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luis A. Di Ciano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elisabet M. Oddo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pablo J. Azurmendi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claudia Silberstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fernando R. Ibarra
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Fernando R. Ibarra, Claudia Silberstein, and Sandra Vlachovsky contributed to the conception and design of the manuscript. Fernando R. Ibarra wrote the first draft of the manuscript. The work was critically revised by Claudia Silberstein, Sandra Vlachovsky, Luis Di Ciano, Elisabet Oddo, and Pablo Azurmendi. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Claudia Silberstein or Fernando R. Ibarra.

Ethics declarations

Ethics Approval

Ethical approval was not required as our study did not involve humans or animals.

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vlachovsky, S.G., Di Ciano, L.A., Oddo, E.M. et al. Role of Female Sex Hormones and Immune Response in Salt-Sensitive Hypertension Development: Evidence from Experimental Models. Curr Hypertens Rep 25, 405–419 (2023). https://doi.org/10.1007/s11906-023-01257-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-023-01257-1

Keywords

Search

Navigation