Skip to main content
SpringerLink
Log in

Glucocorticoid-induced hypertension

  • Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Glucocorticoid-induced hypertension is a common clinical problem that is poorly understood, thus rendering treatment strategies sub-optimal. This form of hypertension has been commonly thought to be mediated by excess sodium and water reabsorption by the renal mineralocorticoid receptor. However, experimental and clinical data in both humans and animal models suggest important roles for the glucocorticoid receptor as well, in both the pathogenesis and maintenance of this hypertension. The glucocorticoid receptor is widely expressed in a number of organ systems relevant to blood pressure regulation, including the kidney, the brain and the vasculature. In vitro studies in isolated kidney tissues as well as in vascular smooth muscle and vascular endothelial cells have attempted to elucidate the molecular physiology of glucocorticoid-induced hypertension, but have generally been limited by the inability to study signaling pathways in an intact organism. More recently, the power of mouse genetics has been employed to examine the tissue-specific contributions of vascular and extra-vascular tissues to this form of hypertension. Here we review recent developments in our understanding of the pathogenesis of glucocorticoid-induced hypertension.

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

Similar content being viewed by others

References

  1. Mantero F, Boscaro M (1992) Glucocorticoid-dependent hypertension. J Steroid Biochem Mol Biol 43:409–413

    Article  PubMed  CAS  Google Scholar 

  2. Baid S, Nieman LK (2004) Glucocorticoid excess and hypertension. Curr Hypertens Rep 6:493–499

    Article  PubMed  Google Scholar 

  3. Etxabe J, Vazquez JA (1994) Morbidity and mortality in Cushing's disease: an epidemiological approach. Clin Endocrinol Oxf 40:479–484

    Article  PubMed  CAS  Google Scholar 

  4. Whitworth JA, Mangos GJ, Kelly JJ (2000) Cushing, cortisol, and cardiovascular disease. Hypertension 36:912–916

    PubMed  CAS  Google Scholar 

  5. Sabharwal P, Fishel RS, Breslow MJ (1998) Adrenal insufficiency—an unusual cause of shock in postoperative patients. Endocr Pract 4:387–390

    PubMed  CAS  Google Scholar 

  6. De Wachter E, Vanbesien J, De Schutter I, Malfroot A, De Schepper J (2003) Rapidly developing Cushing syndrome in a 4-year-old patient during combined treatment with itraconazole and inhaled budesonide. Eur J Pediatr 162:488–489

    Article  PubMed  Google Scholar 

  7. Bertagna X, Bertagna C, Laudat MH, Husson JM, Girard F, Luton JP (1986) Pituitary-adrenal response to the antiglucocorticoid action of RU 486 in Cushing’s syndrome. J Clin Endocrinol Metab 63:639–643

    Article  PubMed  CAS  Google Scholar 

  8. Nieman LK, Chrousos GP, Kellner C, Spitz IM, Nisula BC, Cutler GB, Merriam GR, Bardin CW, Loriaux DL (1985) Successful treatment of Cushing's syndrome with the glucocorticoid antagonist RU 486. J Clin Endocrinol Metab 61:536–540

    Article  PubMed  CAS  Google Scholar 

  9. Sartor O, Cutler GB Jr (1996) Mifepristone: treatment of Cushing's syndrome. Clin Obstet Gynecol 39:506–510

    Article  PubMed  CAS  Google Scholar 

  10. Kalimi M (1989) Role of antiglucocorticoid RU 486 on dexamethasone-induced hypertension in rats. Am J Physiol 256:E682–E685

    PubMed  CAS  Google Scholar 

  11. Grunfeld JP, Eloy L, Moura AM, Ganeval D, Ramos-Frendo B, Worcel M (1985) Effects of antiglucocorticoids on glucocorticoid hypertension in the rat. Hypertension 7:292–299

    PubMed  CAS  Google Scholar 

  12. Mangos GJ, Whitworth JA, Williamson PM, Kelly JJ (2003) Glucocorticoids and the kidney. Nephrology (Carlton) 8:267–273

    Article  CAS  Google Scholar 

  13. Williamson PM, Kelly JJ, Whitworth JA (1996) Dose-response relationships and mineralocorticoid activity in cortisol-induced hypertension in humans. J Hypertens Suppl 14:S37–S41

    Article  PubMed  CAS  Google Scholar 

  14. Montrella-Waybill M, Clore JN, Schoolwerth AC, Watlington CO (1991) Evidence that high dose cortisol-induced Na+ retention in man is not mediated by the mineralocorticoid receptor. J Clin Endocrinol Metab 72:1060–1066

    Article  PubMed  CAS  Google Scholar 

  15. Li M, Wen C, Fraser T, Whitworth JA (1999) Adrenocorticotrophin-induced hypertension: effects of mineralocorticoid and glucocorticoid receptor antagonism. J Hypertens 17:419–426

    Article  PubMed  CAS  Google Scholar 

  16. Campen TJ, Vaughn DA, Fanestil DD (1983) Mineralo- and glucocorticoid effects on renal excretion of electrolytes. Pflugers Arch 399:93–101

    Article  PubMed  CAS  Google Scholar 

  17. Funder JW, Pearce PT, Myles K, Roy LP (1990) Apparent mineralocorticoid excess, pseudohypoaldosteronism, and urinary electrolyte excretion: toward a redefinition of mineralocorticoid action. FASEB J 4:3234–3238

    PubMed  CAS  Google Scholar 

  18. Muller OG, Parnova RG, Centeno G, Rossier BC, Firsov D, Horisberger JD (2003) Mineralocorticoid effects in the kidney: correlation between alphaENaC, GILZ, and Sgk-1 mRNA expression and urinary excretion of Na+ and K+. J Am Soc Nephrol 14:1107–1115

    Article  PubMed  CAS  Google Scholar 

  19. Stewart PM, Corrie JE, Shackleton CH, Edwards CR (1988) Syndrome of apparent mineralocorticoid excess. A defect in the cortisol-cortisone shuttle. J Clin Invest 82:340–349

    Article  PubMed  CAS  Google Scholar 

  20. Todd-Turla KM, Schnermann J, Fejes-Toth G, Naray-Fejes-Toth A, Smart A, Killen PD, Briggs JP (1993) Distribution of mineralocorticoid and glucocorticoid receptor mRNA along the nephron. Am J Physiol 264:F781–F791

    PubMed  CAS  Google Scholar 

  21. Yan K, Kudo A, Hirano H, Watanabe T, Tasaka T, Kataoka S, Nakajima N, Nishibori Y, Shibata T, Kohsaka T, Higashihara E, Tanaka H, Watanabe H, Nagasawa T, Awa S (1999) Subcellular localization of glucocorticoid receptor protein in the human kidney glomerulus. Kidney Int 56:65–73

    Article  PubMed  CAS  Google Scholar 

  22. Baylis C, Handa RK, Sorkin M (1990) Glucocorticoids and control of glomerular filtration rate. Semin Nephrol 10:320–329

    PubMed  CAS  Google Scholar 

  23. Welbourne TC (1990) Glucocorticoid control of ammoniagenesis in the proximal tubule. Semin Nephrol 10:339–349

    PubMed  CAS  Google Scholar 

  24. Rodriguez HJ, Sinha SK, Starling J, Klahr S (1981) Regulation of renal Na+−K+−ATPase in the rat by adrenal steroids. Am J Physiol 241:F186–F195

    PubMed  CAS  Google Scholar 

  25. Freiberg JM, Kinsella J, Sacktor B (1982) Glucocorticoids increase the Na+−H+ exchange and decrease the Na+ gradient-dependent phosphate-uptake systems in renal brush border membrane vesicles. Proc Natl Acad Sci USA 79:4932–4936

    Article  PubMed  CAS  Google Scholar 

  26. Kinsella J, Cujdik T, Sacktor B (1984) Na+−H+ exchange activity in renal brush border membrane vesicles in response to metabolic acidosis: the role of glucocorticoids. Proc Natl Acad Sci USA 81:630–634

    Article  PubMed  CAS  Google Scholar 

  27. Frick A, Durasin I (1980) Proximal tubular reabsorption of inorganic phosphate in adrenalectomized rats. Pflugers Arch 385:189–192

    Article  PubMed  CAS  Google Scholar 

  28. Welch WJ, Ott CE, Guthrie GP Jr, Kotchen TA (1985) Renin secretion and loop of Henle chloride reabsorption in the adrenalectomized rat. Am J Physiol 249:F596–F602

    PubMed  CAS  Google Scholar 

  29. Doucet A, Hus-Citharel A, Morel F (1986) In vitro stimulation of Na-K-ATPase in rat thick ascending limb by dexamethasone. Am J Physiol 251:F851–F857

    PubMed  CAS  Google Scholar 

  30. Stanton BA (1986) Regulation by adrenal corticosteroids of sodium and potassium transport in loop of Henle and distal tubule of rat kidney. J Clin Invest 78:1612–1620

    Article  PubMed  CAS  Google Scholar 

  31. Naray-Fejes-Toth A, Fejes-Toth G (1990) Glucocorticoid receptors mediate mineralocorticoid-like effects in cultured collecting duct cells. Am J Physiol 259:F672–F678

    PubMed  CAS  Google Scholar 

  32. Naray-Fejes-Toth A, Snyder PM, Fejes-Toth G (2004) The kidney-specific WNK1 isoform is induced by aldosterone and stimulates epithelial sodium channel-mediated Na+ transport. Proc Natl Acad Sci USA 101:17434–17439

    Article  PubMed  CAS  Google Scholar 

  33. Li C, Li Y, Liu H, Sun Z, Lu J, Zhao Y (2008) Glucocorticoid repression of human with-no-lysine (K) kinase-4 gene expression is mediated by the negative response elements in the promoter. J Mol Endocrinol 40:3–12

    Article  PubMed  CAS  Google Scholar 

  34. Yang CL, Angell J, Mitchell R, Ellison DH (2003) WNK kinases regulate thiazide-sensitive Na-Cl cotransport. J Clin Invest 111:1039–1045

    PubMed  CAS  Google Scholar 

  35. Wilson FH, Disse-Nicodeme S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP (2001) Human hypertension caused by mutations in WNK kinases. Science 293:1107–1112

    Article  PubMed  CAS  Google Scholar 

  36. Kahle KT, Wilson FH, Leng Q, Lalioti MD, O'Connell AD, Dong K, Rapson AK, MacGregor GG, Giebisch G, Hebert SC, Lifton RP (2003) WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion [see comment]. Nat Genet 35:372–376

    Article  PubMed  CAS  Google Scholar 

  37. Goodwin JE, Zhang J, Velazquez H, Geller DS (2010) The glucocorticoid receptor in the distal nephron is not necessary for the development or maintenance of dexamethasone-induced hypertension. Biochem Biophys Res Commun 394:266–271

    Article  PubMed  CAS  Google Scholar 

  38. Provencher PH, Saltis J, Funder JW (1995) Glucocorticoids but not mineralocorticoids modulate endothelin-1 and angiotensin II binding in SHR vascular smooth muscle cells. J Steroid Biochem Mol Biol 52:219–225

    Article  PubMed  CAS  Google Scholar 

  39. Kornel L, Nelson WA, Manisundaram B, Chigurupati R, Hayashi T (1993) Mechanism of the effects of glucocorticoids and mineralocorticoids on vascular smooth muscle contractility. Steroids 58:580–587

    Article  PubMed  CAS  Google Scholar 

  40. Tsugita M, Iwasaki Y, Nishiyama M, Taguchi T, Shinahara M, Taniguchi Y, Kambayashi M, Terada Y, Hashimoto K (2008) Differential regulation of 11beta-hydroxysteroid dehydrogenase type-1 and −2 gene transcription by proinflammatory cytokines in vascular smooth muscle cells. Life Sci 83:426–432

    Article  PubMed  CAS  Google Scholar 

  41. Wallerath T, Witte K, Schafer SC, Schwarz PM, Prellwitz W, Wohlfart P, Kleinert H, Lehr HA, Lemmer B, Forstermann U (1999) Down-regulation of the expression of endothelial NO synthase is likely to contribute to glucocorticoid-mediated hypertension. Proc Natl Acad Sci USA 96:13357–13362

    Article  PubMed  CAS  Google Scholar 

  42. Ray KP, Searle N (1997) Glucocorticoid inhibition of cytokine-induced E-selectin promoter activation. Biochem Soc Trans 25:189S

    PubMed  CAS  Google Scholar 

  43. Yang S, Zhang L (2004) Glucocorticoids and vascular reactivity. Curr Vasc Pharmacol 2:1–12

    Article  PubMed  Google Scholar 

  44. Sato A, Suzuki H, Nakazato Y, Shibata H, Inagami T, Saruta T (1994) Increased expression of vascular angiotensin II type 1A receptor gene in glucocorticoid-induced hypertension. J Hypertens 12:511–516

    Article  PubMed  CAS  Google Scholar 

  45. Kornel L, Prancan AV, Kanamarlapudi N, Hynes J, Kuzianik E (1995) Study on the mechanisms of glucocorticoid-induced hypertension: glucocorticoids increase transmembrane Ca2+ influx in vascular smooth muscle in vivo. Endocr Res 21:203–210

    Article  PubMed  CAS  Google Scholar 

  46. Molnar GA, Lindschau C, Dubrovska G, Mertens PR, Kirsch T, Quinkler M, Gollasch M, Wresche S, Luft FC, Muller DN, Fiebeler A (2008) Glucocorticoid-related signaling effects in vascular smooth muscle cells. Hypertension 51:1372–1378

    Article  PubMed  CAS  Google Scholar 

  47. Ong SL, Zhang Y, Sutton M, Whitworth JA (2009) Hemodynamics of dexamethasone-induced hypertension in the rat. Hypertens Res 32:889–894

    Article  PubMed  CAS  Google Scholar 

  48. Cuspidi C, Meani S, Salerno M, Valerio C, Fusi V, Severgnini B, Lonati L, Magrini F, Zanchetti A (2004) Cardiovascular target organ damage in essential hypertensives with or without reproducible nocturnal fall in blood pressure. J Hypertens 22:273–280

    Article  PubMed  CAS  Google Scholar 

  49. Imai Y, Abe K, Sasaki S, Minami N, Munakata M, Nihei M, Sekino H, Yoshinaga K (1989) Exogenous glucocorticoid eliminates or reverses circadian blood pressure variations. J Hypertens 7:113–120

    PubMed  CAS  Google Scholar 

  50. Piovesan A, Panarelli M, Terzolo M, Osella G, Matrella C, Paccotti P, Angeli A (1990) 24-hour profiles of blood pressure and heart rate in Cushing's syndrome: relationship between cortisol and cardiovascular rhythmicities. Chronobiol Int 7:263–265

    Article  PubMed  CAS  Google Scholar 

  51. Fallo F, Fanelli G, Cipolla A, Betterle C, Boscaro M, Sonino N (1994) 24-hour blood pressure profile in Addison's disease. Am J Hypertens 7:1105–1109

    PubMed  CAS  Google Scholar 

  52. Wallerath T, Godecke A, Molojavyi A, Li H, Schrader J, Forstermann U (2004) Dexamethasone lacks effect on blood pressure in mice with a disrupted endothelial NO synthase gene. Nitric Oxide 10:36–41

    Article  PubMed  CAS  Google Scholar 

  53. Mitchell BM, Dorrance AM, Mack EA, Webb RC (2004) Glucocorticoids decrease GTP cyclohydrolase and tetrahydrobiopterin-dependent vasorelaxation through glucocorticoid receptors. J Cardiovasc Pharmacol 43:8–13

    Article  PubMed  CAS  Google Scholar 

  54. Yudt MR, Cidlowski JA (2002) The glucocorticoid receptor: coding a diversity of proteins and responses through a single gene. Mol Endocrinol 16:1719–1726

    Article  PubMed  CAS  Google Scholar 

  55. Goodwin JE, Zhang J, Geller DS (2008) A critical role for vascular smooth muscle in acute glucocorticoid-induced hypertension. J Am Soc Nephrol 19:1291–1299

    Article  PubMed  CAS  Google Scholar 

  56. Goodwin J, Zhang J, Gonzalez D, Albinsson S, Geller DS (2011) Knockout of the vascular endothelial glucocorticoid receptor abrogates dexamethasone-induced hypertension. J Hypertens 29:1347–1356

    Google Scholar 

  57. Aras-Lopez R, Xavier FE, Ferrer M, Balfagon G (2009) Dexamethasone decreases neuronal nitric oxide release in mesenteric arteries from hypertensive rats through decreased protein kinase C activation. Clin Sci (Lond) 117:305–312

    Article  CAS  Google Scholar 

  58. Rask E, Olsson T, Soderberg S, Andrew R, Livingstone DE, Johnson O, Walker BR (2001) Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab 86:1418–1421

    Article  PubMed  CAS  Google Scholar 

  59. Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS (2001) A transgenic model of visceral obesity and the metabolic syndrome. Science 294:2166–2170

    Article  PubMed  CAS  Google Scholar 

  60. Paterson JM, Morton NM, Fievet C, Kenyon CJ, Holmes MC, Staels B, Seckl JR, Mullins JJ (2004) Metabolic syndrome without obesity: hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice. Proc Natl Acad Sci USA 101:7088–7093

    Article  PubMed  CAS  Google Scholar 

  61. Zhang J, Ge R, Matte-Martone C, Goodwin J, Shlomchik WD, Mamula MJ, Kooshkabadi A, Hardy MP, Geller D (2009) Characterization of a novel gain of function glucocorticoid receptor knock-in mouse. J Biol Chem 284:6249–6259

    Article  PubMed  CAS  Google Scholar 

  62. Krug AW, Ehrhart-Bornstein M (2008) Adrenocortical dysfunction in obesity and the metabolic syndrome. Horm Metab Res 40:515–517

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Nephrology, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, PO Box 208064, New Haven, CT, 06520, USA

    Julie E. Goodwin

  2. Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, CT, 06520–8029, USA

    David S. Geller

  3. Department of Medicine, Veterans Affairs Medical Center, West Haven, CT, 06516, USA

    David S. Geller

Authors
  1. Julie E. Goodwin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David S. Geller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Julie E. Goodwin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goodwin, J.E., Geller, D.S. Glucocorticoid-induced hypertension. Pediatr Nephrol 27, 1059–1066 (2012). https://doi.org/10.1007/s00467-011-1928-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-011-1928-4

Keywords

Search

Navigation