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.

  • Mini Review
  • Mini review series: Current topic in Hypertension
  • Published:

Emerging topics on basic research in hypertension: interorgan communication and the need for interresearcher collaboration

Abstract

The pathogenesis of hypertension is multifactorial and highly complex. Basic research plays critical roles in elucidating the complex pathogenesis of hypertension and developing its treatment. This review covers recent topics in basic research related to hypertension in the following six parts: brain/autonomic nervous system, kidney, vascular system, potential treatments, extracellular vesicles, and gut microbiota. The brain receives afferent nerve inputs from peripheral organs, including the heart, kidneys, and adipose tissue, and humoral inputs from circulating factors such as proinflammatory cytokines and leptin, which are involved in the regulation of central sympathetic outflow. In the kidneys, changes in Wnt/β-catenin signaling have been reported in several hypertensive models. New findings on the renin-angiotensin-aldosterone system in the kidneys have also been reported. Sirtuin 6, which participates in various cellular functions, including DNA repair, has been shown to have protective effects on the vascular system. Skin water conservation, mediated by skin vasoconstriction and the accumulation of osmolytes such as sodium, has been found to contribute to hypertension. Studies of rivaroxaban and sodium-glucose cotransporter-2 inhibitors as drug repositioning candidates have been performed. Extracellular vesicles have been shown to be involved in novel diagnostic approaches and treatments for hypertension as well as other diseases. In gut microbiota studies, interactions between microbiota and antihypertensive drugs and potential pathophysiology linking microbiota and COVID-19 have been reported. It can be seen that inter-organ communication has received particular attention from these recent research topics. To truly understand the pathogenesis of hypertension and to develop treatments for conquering hypertension, interresearcher communication and collaboration should be further facilitated.

This mini-review focuses on recent topics on basic research in hypertension from the several points of view. The recent topics indicate that inter-organ communication has received particular attention. Interresearcher communication and collaboration should also be further facilitated to truly understand the complex pathogenesis of hypertension and to develop the treatments.

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

Access options

Buy this article

USD 39.95

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Hirooka Y. Sympathetic activation in hypertension: importance of the central nervous system. Am J Hypertens. 2020;33:914–26.

    Article  CAS  Google Scholar 

  2. Katsurada K, Shinohara K, Aoki J, Nanto S, Kario K. Renal denervation: basic and clinical evidence. Hypertens Res. 2022;45:198–209.

    Article  Google Scholar 

  3. Kario K, Hoshide S, Mogi M. A recent advance in Renal denervation to clinical practice. Hypertens Res. 2022 (e-pub ahead of print 20221005; https://doi.org/10.1038/s41440-022-01050-8).

  4. Chen WW, Xiong XQ, Chen Q, Li YH, Kang YM, Zhu GQ. Cardiac sympathetic afferent reflex and its implications for sympathetic activation in chronic heart failure and hypertension. Acta Physiol (Oxf). 2015;213:778–94.

    Article  CAS  Google Scholar 

  5. Zhu GQ, Xu Y, Zhou LM, Li YH, Fan LM, Wang W, et al. Enhanced cardiac sympathetic afferent reflex involved in sympathetic overactivity in renovascular hypertensive rats. Exp Physiol. 2009;94:785–94.

    Article  Google Scholar 

  6. Wang HJ, Wang W, Cornish KG, Rozanski GJ, Zucker IH. Cardiac sympathetic afferent denervation attenuates cardiac remodeling and improves cardiovascular dysfunction in rats with heart failure. Hypertension. 2014;64:745–55.

    Article  CAS  Google Scholar 

  7. Zahner MR, Li DP, Chen SR, Pan HL. Cardiac vanilloid receptor 1-expressing afferent nerves and their role in the cardiogenic sympathetic reflex in rats. J Physiol. 2003;551:515–23.

    Article  CAS  Google Scholar 

  8. Shibata R, Shinohara K, Ikeda S, Iyonaga T, Matsuura T, Kashihara S, et al. Transient receptor potential vanilloid 1-expressing cardiac afferent nerves may contribute to cardiac hypertrophy in accompany with an increased expression of brain-derived neurotrophic factor within nucleus tractus solitarius in a pressure overload model. Clin Exp Hypertens. 2022;44:249–57.

    Article  CAS  Google Scholar 

  9. Xiong XQ, Chen WW, Zhu GQ. Adipose afferent reflex: sympathetic activation and obesity hypertension. Acta Physiol (Oxf). 2014;210:468–78.

    Article  CAS  Google Scholar 

  10. Cao W, Shi M, Wu L, Li J, Yang Z, Liu Y, et al. Adipocytes initiate an adipose-cerebral-peripheral sympathetic reflex to induce insulin resistance during high-fat feeding. Clin Sci (Lond). 2019;133:1883–99.

    Article  CAS  Google Scholar 

  11. Dalmasso C, Leachman JR, Osborn JL, Loria AS. Sensory signals mediating high blood pressure via sympathetic activation: role of adipose afferent reflex. Am J Physiol Regul Integr Comp Physiol. 2020;318:R379–r389.

    Article  CAS  Google Scholar 

  12. Dalmasso C, Leachman JR, Ghuneim S, Ahmed N, Schneider ER, Thibault O, et al. Epididymal fat-derived sympathoexcitatory signals exacerbate neurogenic hypertension in obese male mice exposed to early life stress. Hypertension. 2021;78:1434–49.

    Article  CAS  Google Scholar 

  13. Asirvatham-Jeyaraj N, Gauthier MM, Banek CT, Ramesh A, Garver H, Fink GD, et al. Renal denervation and celiac ganglionectomy decrease mean arterial pressure similarly in genetically hypertensive schlager (BPH/2J) mice. Hypertension. 2021;77:519–28.

    Article  CAS  Google Scholar 

  14. Foss JD, Fink GD, Osborn JW. Reversal of genetic salt-sensitive hypertension by targeted sympathetic ablation. Hypertension. 2013;61:806–11.

    Article  CAS  Google Scholar 

  15. King AJ, Osborn JW, Fink GD. Splanchnic circulation is a critical neural target in angiotensin II salt hypertension in rats. Hypertension. 2007;50:547–56.

    Article  CAS  Google Scholar 

  16. Kandlikar SS, Fink GD. Splanchnic sympathetic nerves in the development of mild DOCA-salt hypertension. Am J Physiol Heart Circ Physiol. 2011;301:H1965–73.

    Article  CAS  Google Scholar 

  17. Osborn JW, Fink GD, Kuroki MT. Neural mechanisms of angiotensin II-salt hypertension: implications for therapies targeting neural control of the splanchnic circulation. Curr Hypertens Rep. 2011;13:221–8.

    Article  Google Scholar 

  18. Randhawa PK, Jaggi AS. TRPV1 channels in cardiovascular system: a double edged sword? Int J Cardiol. 2017;228:103–13.

    Article  Google Scholar 

  19. Bisognano JD, Bakris G, Nadim MK, Sanchez L, Kroon AA, Schafer J, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol. 2011;58:765–73.

    Article  Google Scholar 

  20. Illig KA, Levy M, Sanchez L, Trachiotis GD, Shanley C, Irwin E, et al. An implantable carotid sinus stimulator for drug-resistant hypertension: surgical technique and short-term outcome from the multicenter phase II Rheos feasibility trial. J Vasc Surg. 2006;44:1213–8.

    Article  Google Scholar 

  21. de Leeuw PW, Alnima T, Lovett E, Sica D, Bisognano J, Haller H, et al. Bilateral or unilateral stimulation for baroreflex activation therapy. Hypertension. 2015;65:187–92.

    Article  Google Scholar 

  22. Domingos-Souza G, Santos-Almeida FM, Meschiari CA, Ferreira NS, Pereira CA, Pestana-Oliveira N, et al. The ability of baroreflex activation to improve blood pressure and resistance vessel function in spontaneously hypertensive rats is dependent on stimulation parameters. Hypertens Res. 2021;44:932–40.

    Article  CAS  Google Scholar 

  23. Cao Y, Yu Y, Xue B, Wang Y, Chen X, Beltz TG, et al. IL (Interleukin)-17A acts in the brain to drive neuroinflammation, sympathetic activation, and hypertension. Hypertension. 2021;78:1450–62.

    Article  CAS  Google Scholar 

  24. Wei SG, Zhang ZH, Beltz TG, Yu Y, Johnson AK, Felder RB. Subfornical organ mediates sympathetic and hemodynamic responses to blood-borne proinflammatory cytokines. Hypertension. 2013;62:118–25.

    Article  CAS  Google Scholar 

  25. Wei SG, Yu Y, Felder RB. Blood-borne interleukin-1beta acts upon the subfornical organ to upregulate the sympathoexcitatory milieu of the hypothalamic paraventricular nucleus. Am J Physiol Regul Integr Comp Physiol. 2017. https://doi.org/10.1152/ajpregu.00211.2017.

  26. Wei SG, Yu Y, Zhang ZH, Felder RB. Proinflammatory cytokines upregulate sympathoexcitatory mechanisms in the subfornical organ of the rat. Hypertension. 2015;65:1126–33.

    Article  CAS  Google Scholar 

  27. Iyonaga T, Shinohara K, Mastuura T, Hirooka Y, Tsutsui H. Brain perivascular macrophages contribute to the development of hypertension in stroke-prone spontaneously hypertensive rats via sympathetic activation. Hypertens Res. 2020;43:99–110.

    Article  CAS  Google Scholar 

  28. Gruber T, Pan C, Contreras RE, Wiedemann T, Morgan DA, Skowronski AA, et al. Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension. Cell Metab. 2021;33:1155–.e1110.

    Article  CAS  Google Scholar 

  29. Kasacka I, Piotrowska Z, Domian N, Acewicz M, Lewandowska A. Canonical Wnt signaling in the kidney in different hypertension models. Hypertens Res. 2021;44:1054–66.

    Article  CAS  Google Scholar 

  30. Schunk SJ, Floege J, Fliser D, Speer T. WNT-β-catenin signalling - a versatile player in kidney injury and repair. Nat Rev Nephrol. 2021;17:172–84.

    Article  CAS  Google Scholar 

  31. Nagasu H. Importance of wnt-catenin signaling in hypertensive kidney diseases. Hypertens Res. 2021;44:1546–7.

    Article  CAS  Google Scholar 

  32. Matsusaka T, Niimura F, Shimizu A, Pastan I, Saito A, Kobori H, et al. Liver angiotensinogen is the primary source of renal angiotensin II. J Am Soc Nephrol. 2012;23:1181–9.

    Article  CAS  Google Scholar 

  33. Matsuyama T, Ohashi N, Aoki T, Ishigaki S, Isobe S, Sato T, et al. Circadian rhythm of the intrarenal renin-angiotensin system is caused by glomerular filtration of liver-derived angiotensinogen depending on glomerular capillary pressure in adriamycin nephropathy rats. Hypertens Res. 2021;44:618–27.

    Article  CAS  Google Scholar 

  34. Maeoka Y, Su XT, Wang WH, Duan XP, Sharma A, Li N, et al. Mineralocorticoid receptor antagonists cause natriuresis in the absence of aldosterone. Hypertension. 2022;79:1423–34.

    Article  CAS  Google Scholar 

  35. Grootaert MOJ, Finigan A, Figg NL, Uryga AK, Bennett MR. SIRT6 protects smooth muscle cells from senescence and reduces atherosclerosis. Circ Res. 2021;128:474–91.

    Article  CAS  Google Scholar 

  36. Liu X, Jiang D, Huang W, Teng P, Zhang H, Wei C, et al. Sirtuin 6 attenuates angiotensin II-induced vascular adventitial aging in rat aortae by suppressing the NF-kappaB pathway. Hypertens Res. 2021;44:770–80.

    Article  CAS  Google Scholar 

  37. Li W, Feng W, Su X, Luo D, Li Z, Zhou Y, et al. SIRT6 protects vascular smooth muscle cells from osteogenic transdifferentiation via Runx2 in chronic kidney disease. J Clin Invest. 2022;132:e150051.

  38. Ogura T, Kitada K, Morisawa N, Fujisawa Y, Kidoguchi S, Nakano D, et al. Contributions of renal water loss and skin water conservation to blood pressure elevation in spontaneously hypertensive rats. Hypertens Res. 2022; https://doi.org/10.1038/s41440-022-01044-6).

  39. Kovarik JJ, Morisawa N, Wild J, Marton A, Takase-Minegishi K, Minegishi S, et al. Adaptive physiological water conservation explains hypertension and muscle catabolism in experimental chronic renal failure. Acta Physiol (Oxf). 2021;232:e13629.

    Article  CAS  Google Scholar 

  40. Wild J, Jung R, Knopp T, Efentakis P, Benaki D, Grill A, et al. Aestivation motifs explain hypertension and muscle mass loss in mice with psoriatic skin barrier defect. Acta Physiol (Oxf). 2021;232:e13628.

    Article  CAS  Google Scholar 

  41. Daci A, Da Dalt L, Alaj R, Shurdhiqi S, Neziri B, Ferizi R, et al. Rivaroxaban improves vascular response in LPS-induced acute inflammation in experimental models. PLoS One. 2020;15:e0240669.

    Article  CAS  Google Scholar 

  42. Nakanishi N, Kaikita K, Ishii M, Oimatsu Y, Mitsuse T, Ito M, et al. Cardioprotective effects of rivaroxaban on cardiac remodeling after experimental myocardial infarction in mice. Circ Rep. 2020;2:158–66.

    Article  Google Scholar 

  43. Narita M, Hanada K, Kawamura Y, Ichikawa H, Sakai S, Yokono Y, et al. Rivaroxaban attenuates cardiac hypertrophy by inhibiting protease-activated receptor-2 signaling in renin-overexpressing hypertensive mice. Hypertens Res. 2021;44:1261–73.

    Article  CAS  Google Scholar 

  44. Kravtsova O, Bohovyk R, Levchenko V, Palygin O, Klemens CA, Rieg T, et al. SGLT2 inhibition effect on salt-induced hypertension, RAAS, and Na(+) transport in Dahl SS rats. Am J Physiol Ren Physiol. 2022;322:F692–f707.

    Article  CAS  Google Scholar 

  45. Zhao Y, Li L, Lu Z, Hu Y, Zhang H, Sun F, et al. Sodium-glucose cotransporter 2 inhibitor canagliflozin antagonizes salt-sensitive hypertension through modifying transient receptor potential channels 3 mediated vascular calcium handling. J Am Heart Assoc. 2022;11:e025328.

    Article  Google Scholar 

  46. Ochiai-Homma F, Kuribayashi-Okuma E, Tsurutani Y, Ishizawa K, Fujii W, Odajima K, et al. Characterization of pendrin in urinary extracellular vesicles in a rat model of aldosterone excess and in human primary aldosteronism. Hypertens Res. 2021;44:1557–67.

    Article  CAS  Google Scholar 

  47. Lugo-Gavidia LM, Burger D, Nolde JM, Carnagarin R, Chan J, Bosio E, et al. Platelet-derived extracellular vesicles correlate with therapy-induced nocturnal blood pressure changes. J Hypertens. 2022;40:2210–8.

    Article  CAS  Google Scholar 

  48. Chi C, Fu H, Li YH, Zhang GY, Zeng FY, Ji QX, et al. Exerkine fibronectin type-III domain-containing protein 5/irisin-enriched extracellular vesicles delay vascular ageing by increasing SIRT6 stability. Eur Heart J. 2022; https://doi.org/10.1093/eurheartj/ehac431).

  49. Mathieu M, Martin-Jaular L, Lavieu G, Théry C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21:9–17.

    Article  CAS  Google Scholar 

  50. Wang C, Wu H, Xing Y, Ye Y, He F, Yin Q, et al. Endothelial-derived extracellular microRNA-92a promotes arterial stiffness by regulating phenotype changes of vascular smooth muscle cells. Sci Rep. 2022;12:344.

    Article  CAS  Google Scholar 

  51. Mishima E, Abe T. Role of the microbiota in hypertension and antihypertensive drug metabolism. Hypertens Res. 2022;45:246–53.

    Article  CAS  Google Scholar 

  52. Kyoung J, Atluri RR, Yang T. Resistance to antihypertensive drugs: is gut microbiota the missing link? Hypertension. 2022;79:2138–47.

    Article  CAS  Google Scholar 

  53. Wu H, Lam TYC, Shum TF, Tsai TY, Chiou J. Hypotensive effect of captopril on deoxycorticosterone acetate-salt-induced hypertensive rat is associated with gut microbiota alteration. Hypertens Res. 2022;45:270–82.

    Article  CAS  Google Scholar 

  54. Yang T, Mei X, Tackie-Yarboi E, Akere MT, Kyoung J, Mell B, et al. Identification of a gut commensal that compromises the blood pressure-lowering effect of Ester angiotensin-converting enzyme inhibitors. Hypertension . 2022;79:1591–601.

    Article  CAS  Google Scholar 

  55. Kai H, Kai M, Niiyama H, Okina N, Sasaki M, Maeda T, et al. Overexpression of angiotensin-converting enzyme 2 by renin-angiotensin system inhibitors. Truth or myth? A systematic review of animal studies. Hypertens Res. 2021;44:955–68.

    Article  CAS  Google Scholar 

  56. Shibata S, Arima H, Asayama K, Hoshide S, Ichihara A, Ishimitsu T, et al. Hypertension and related diseases in the era of COVID-19: a report from the Japanese Society of Hypertension Task Force on COVID-19. Hypertension Res. 2020;43:1028–46.

    Article  CAS  Google Scholar 

  57. Ishida M. How to deal with hypertension in the COVID-19 era—the impact “ON” and “OF” hypertension. Hypertension Res. 2022;45:548–50.

    Article  CAS  Google Scholar 

  58. Wojciechowska W, Terlecki M, Klocek M, Pac A, Olszanecka A, Stolarz-Skrzypek K, et al. Impact of arterial hypertension and use of antihypertensive pharmacotherapy on mortality in patients hospitalized due to COVID-19: the CRACoV-HHS study. Hypertension. 2022;79:2601–10.

    Article  CAS  Google Scholar 

  59. Li J, Stevens BR, Richards EM, Raizada MK. SARS-CoV-2 receptor ACE2 (Angiotensin-Converting Enzyme 2) is upregulated in colonic organoids from hypertensive rats. Hypertension. 2020;76:e26–8.

    Article  CAS  Google Scholar 

  60. Sharma RK, Stevens BR, Obukhov AG, Grant MB, Oudit GY, Li Q, et al. ACE2 (Angiotensin-Converting Enzyme 2) in cardiopulmonary diseases: ramifications for the control of SARS-CoV-2. Hypertension. 2020;76:651–61.

    Article  CAS  Google Scholar 

  61. Li J, Richards EM, Handberg EM, Pepine CJ, Raizada MK. Butyrate regulates COVID-19-relevant genes in gut epithelial organoids from normotensive rats. Hypertension. 2021;77:e13–6.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

I sincerely appreciate the editors of Hypertension Research for giving me the opportunity to write this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Keisuke Shinohara.

Ethics declarations

Conflict of interests

The author declares no competing interests.

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

Shinohara, K. Emerging topics on basic research in hypertension: interorgan communication and the need for interresearcher collaboration. Hypertens Res 46, 638–645 (2023). https://doi.org/10.1038/s41440-023-01176-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41440-023-01176-3

Keywords

Search

Quick links