Under pressure: the search for the essential mechanisms of hypertension

Article metrics

Abstract

High blood pressure, or hypertension, is a very common disorder with a substantial impact on public health because of its associated complications. Despite the high prevalence of essential hypertension and years of research, the basic causes remain obscure. Here I review recent advances in understanding the pathophysiology of hypertension. I present a general overview of the field and, by necessity, use broad strokes to portray recent progress and place it in context. For this purpose, I use illustrative examples from the large number of important developments in hypertension research over the last five years. The intent of this review is to provide a sense of where the field is progressing, with an emphasis on work that sheds light on pathogenic mechanisms and that is therefore likely to inform new translational advances.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The proposed three-compartment model for the disposition of sodium.
Figure 2: Key vascular signaling pathways in hypertension.
Figure 3: Regulatory mechanisms for blood pressure are targets for therapy in hypertension.

References

  1. 1

    Lawes, C.M., Vander Hoorn, S. & Rodgers, A. Global burden of blood-pressure related disease. Lancet 371, 1513–1518 (2008).

  2. 2

    The VA Cooperative Study Group. Effects of treatment on morbidity of hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. J. Am. Med. Assoc. 202, 1028–1034 (1967).

  3. 3

    Chobanian, A. The hypertension paradox: more uncontrolled disease despite improving therapy. N. Engl. J. Med. 361, 878–887 (2009).

  4. 4

    Guyton, A.C. Blood pressure control—special role of the kidneys and body fluids. Science 252, 1813–1816 (1991).

  5. 5

    Meneton, P., Jeunmaitre, X., de Wardener, H. & MacGregor, G. LInks between dietary salt intake, renal salt handling, blood pressure and cardiovascular disease. Physiol. Rev. 85, 679–715 (2005).

  6. 6

    The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Group & the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J. Am. Med. Assoc. 288, 2981–2997 (2002).

  7. 7

    Rettig, R. & Grisk, O. The kidney as a determinant of genetic hypertension: evidence from renal transplantation studies. Hypertension 46, 463–468 (2005).

  8. 8

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

  9. 9

    Crowley, S.D. et al. Distinct roles for the kidney and systemic tissues in blood pressure regulation by the renin-angiotensin system. J. Clin. Invest. 115, 1092–1099 (2005).

  10. 10

    Gurley, S.B. et al. AT1A Angiotensin receptors in the renal proximal tubule regulate blood pressure. Cell Metab. 13, 469–475 (2011).

  11. 11

    Li, H. et al. Renal proximal tubule angiotensin AT1A receptors regulate blood pressure. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R1209–R1211 (2011).

  12. 12

    Navar, L.G., Kobori, H., Prieto, M.C. & Gonzalez-Villalobos, R.A. Intratubular renin-angiotensin system in hypertension. Hypertension 57, 355–362 (2011).

  13. 13

    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).

  14. 14

    Guzik, T.J. et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J. Exp. Med. 204, 2449–2460 (2007).

  15. 15

    Cowley, A.W. Long-term control of arterial blood pressure. Physiol. Rev. 72, 231–300 (1992).

  16. 16

    Wirth, A. et al. G12–G13-LARG–mediated signaling in vascular smooth muscle is required for salt-induced hypertension. Nat. Med. 14, 64–68 (2008).

  17. 17

    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).

  18. 18

    Packard, R.R., Lichtman, A.H. & Libby, P. Innate and adaptive immunity in atherosclerosis. Semin. Immunopathol. 31, 5–22 (2009).

  19. 19

    Muller, D.N. et al. Immunosuppressive treatment protects against angiotensin II–induced renal damage. Am. J. Pathol. 161, 1679–1693 (2002).

  20. 20

    Nataraj, C. et al. Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway. J. Clin. Invest. 104, 1693–1701 (1999).

  21. 21

    Madhur, M.S. et al. Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension 55, 500–507 (2010).

  22. 22

    Crowley, S. et al. Lymphocyte responses exacerbate angiotensin II-dependent hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R1089–R1097 (2009).

  23. 23

    Vinh, A. et al. Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension. Circulation 122, 2529–2537 (2010).

  24. 24

    Marvar, P.J. et al. Central and peripheral mechanisms of T-lymphocyte activation and vascular inflammation produced by angiotensin II induced hypertension. Circ. Res. 107, 263–270 (2010).

  25. 25

    Lifton, R.P., Gharavi, A. & Geller, D. Molecular mechanisms of human hypertension. Cell 104, 545–556 (2001).

  26. 26

    Levy, D. et al. Genome-wide association study of blood pressure and hypertension. Nat. Genet. 41, 677–687 (2009).

  27. 27

    Newton-Cheh, C. et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat. Genet. 41, 666–676 (2009).

  28. 28

    Kato, N. et al. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians. Nat. Genet. 43, 531–538 (2011).

  29. 29

    The International Consortium for Blood Pressure Genome-Wide Association Studies et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature 478, 103–109 (2011).

  30. 30

    Auchus, R.J. The genetics, pathophyioslogy and management of human deficiencies of P450c17. Endocrinol. Metab. Clin. North Am. 30, 101–119 (2001).

  31. 31

    John, S.W. et al. Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science 267, 679–681 (1995).

  32. 32

    Newton-Cheh, C. et al. Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure. Nat. Genet. 41, 348–353 (2009).

  33. 33

    Ge, Y. et al. Collecting duct specific knockout of the ednothelin B recpetor causes hypertension and sodium retention. Am. J. Physiol. Renal. Physiol. 291, F1274–F1280 (2006).

  34. 34

    Gudbjartsson, D.F. et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat. Genet. 41, 342–347 (2009).

  35. 35

    Cirulli, E.T. & Goldstein, D.B. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat. Rev. Genet. 11, 415–425 (2010).

  36. 36

    Ji, W. et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat. Genet. 40, 592–599 (2008).

  37. 37

    Choi, M. et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331, 768–772 (2011).

  38. 38

    Sacks, F.M. et al. Effects on blood pressure of reduced dietary sodium and the dietary approches to stop hypertension (DASH) diet. N. Engl. J. Med. 344, 3–10 (2001).

  39. 39

    Tissot, A.C. et al. Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study. Lancet 371, 821–827 (2008).

  40. 40

    Malpas, S.C. Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol. Rev. 90, 513–557 (2010).

  41. 41

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

  42. 42

    Simplicity HTN-2 Investigators et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (the Simplicity HTN-2 Trial): a randomised controlled trial. Lancet 376, 1903–1909 (2010).

  43. 43

    Krum, H. et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 373, 1275–1281 (2009).

  44. 44

    Heusser, K. et al. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension 55, 619–626 (2010).

Download references

Acknowledgements

The author's work in this area has been supported by the US National Institutes of Health (HL056122), the Veteran's Affairs Research Administration and the Edna and Fred L. Mandel Jr. Foundation.

Author information

Correspondence to Thomas M Coffman.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Further reading