Endothelial Cell Swelling by Aldosterone


There is accumulating evidence that mineralocorticoids not only act on kidney but also on the cardiovascular system. We investigated the response of human umbilical venous endothelial cells (HUVECs) to aldosterone at a time scale of 20 minutes in absence and presence of the aldosterone antagonist spironolactone or other transport inhibitors. We applied atomic force microscopy (AFM), which measures cell volume and volume shifts between cytosol and cell nucleus. We observed an immediate cell volume increase (about 10%) approximately 1 min after addition of aldosterone (0.1 µmol/l), approaching a maximum (about 18%) 10 min after aldosterone treatment. Cell volume returned to normal 20 min after hormone exposure. Spironolactone (1 µmol/l) or amiloride (1 µmol/l) prevented the late aldosterone-induced volume changes but not the immediate change observed 1 min after hormone exposure. AFM revealed nuclear swelling 5 min after aldosterone addition, followed by nuclear shrinkage 15 min later. The Na+/H+ exchange blocker cariporide (10 µmol/l) was ineffective. We conclude: (i) Aldosterone induces immediate (1 min) swelling independently of plasma membrane Na+ channels and intracellular mineralocorticoid receptors followed by late mineralocorticoid receptor- and Na+-channel-dependent swelling. (ii) Intracellular macromolecule shifts cause the changes in cell volume. (iii) Both amiloride and spironolactone may be useful for medical applications to prevent aldosterone-induced vasculopathies.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6


  1. 1

    R.W. Berliner G. Giebisch (2001) ArticleTitleRemembrances of renal potassium transport. J. Membrane Biol. 184 225–232 Occurrence Handle10.1007/s00232-001-0091-4 Occurrence Handle1:CAS:528:DC%2BD38XktlGqtw%3D%3D

    Article  CAS  Google Scholar 

  2. 2

    G.A. Brown M.D. Vukovich E.R. Martini M.L. Kohut W.D. Franke D.A. Jackson D.S. King (2000) ArticleTitleEndocrine responses to chronic androstenedione intake in 30- to 56-year-old men. J. Clin. Endocrinol. Metab. 85 4074–4080 Occurrence Handle1:CAS:528:DC%2BD3cXotlWntbs%3D Occurrence Handle11095435

    CAS  PubMed  Google Scholar 

  3. 3

    C.M. Doolan G.C. O’Sullivan B.J. Harvey (1998) ArticleTitleRapid effects of corticosteroids on cytosolic protein kinase C and intracellular calcium concentration in human distal colon. Mol. Cell Endocrinol. 138 71–79 Occurrence Handle10.1016/S0303-7207(98)00020-3 Occurrence Handle1:CAS:528:DyaK1cXjtVKksbo%3D Occurrence Handle9685216

    Article  CAS  PubMed  Google Scholar 

  4. 4

    D. Duprez M. De Buyzere E.R. Rietzschel D.L. Clement (2000) ArticleTitleAldosterone and vascular damage. Curr. Hypertens. Rep. 2 327–334 Occurrence Handle1:STN:280:DC%2BD3cvpsV2htA%3D%3D Occurrence Handle10981167

    CAS  PubMed  Google Scholar 

  5. 5

    M. Epstein (2001) ArticleTitleAldosterone as a mediator of progressive renal disease: pathogenetic and clinical implications. Am. J. Kidney Dis. 37 677–688 Occurrence Handle1:CAS:528:DC%2BD3MXjtFWqs70%3D Occurrence Handle11273866

    CAS  PubMed  Google Scholar 

  6. 6

    G. Frindt T. McNair A. Dahlmann E. Jacobs-Palmer L.G. Palmer (2002) ArticleTitleEpithelial Na channels and short-term renal response to salt deprivation. Am. J. Physiol. 283 F717–F726

    Google Scholar 

  7. 7

    N. Gamper S.M. Huber K. Badawi F. Lang (2000) ArticleTitleCell volume-sensitive sodium channels upregulated by glucocorticoids in U937 macrophages. Pfluegers Arch. 441 281–286 Occurrence Handle10.1007/s004240000410 Occurrence Handle1:CAS:528:DC%2BD3cXos1KhtLc%3D

    Article  CAS  Google Scholar 

  8. 8

    M. Gekle N. Golenhofen H. Oberleithner S. Silbernagl (1996) ArticleTitleRapid activation of Na+/H+ exchange by aldosterone in renal epithelial cells requires Ca2+ and stimulation of a plasma membrane proton conductance. Proc. Natl. Acad. Sci USA 93 10500–10504 Occurrence Handle10.1073/pnas.93.19.10500 Occurrence Handle1:CAS:528:DyaK28XlslGrs7o%3D Occurrence Handle8816833

    Article  CAS  PubMed  Google Scholar 

  9. 9

    T. Goerge A. Niemeyer P. Rogge R. Ossig H. Oberleithner S.W. Schneider (2002) ArticleTitleSecretion pores in human endothelial cells during acute hypoxia. J. Membrane Biol. 187 203–211 Occurrence Handle10.1007/s00232-001-0164-4 Occurrence Handle1:CAS:528:DC%2BD38Xks1ylsrs%3D

    Article  CAS  Google Scholar 

  10. 10

    N. Golestaneh C. Klein F. Valamanesh G. Suarez M.K. Agarwal M. Mirshahi (2001) ArticleTitleMineralocorticoid receptor-mediated signaling regulates the ion gated sodium channel in vascular endothelial cells and requires an intact cytoskeleton. Biochem. Biophys. Res. Commun. 280 1300–1306 Occurrence Handle10.1006/bbrc.2001.4275 Occurrence Handle1:CAS:528:DC%2BD3MXptlCrtQ%3D%3D Occurrence Handle11162670

    Article  CAS  PubMed  Google Scholar 

  11. 11

    H. Hatakeyama I. Miyamori T. Fujita Y. Takeda R. Takeda H. Yamamoto (1994) ArticleTitleVascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J. Biol. Chem. 269 24316–24320 Occurrence Handle1:CAS:528:DyaK2cXmt1elsro%3D Occurrence Handle7929089

    CAS  PubMed  Google Scholar 

  12. 12

    H. Hayashi K. Szaszi S. Grinstein (2002) ArticleTitleMultiple modes of regulation of Na+/H+ exchangers. Ann. N. Y. Acad. Sci. 976 248–258 Occurrence Handle1:CAS:528:DC%2BD3sXht1yhsro%3D Occurrence Handle12502567

    CAS  PubMed  Google Scholar 

  13. 13

    E.A. Jaffe R.L. Nachman C.G. Becker C.R. Minick (1973) ArticleTitleCulture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J. Clin. Invest 52 2745–2756 Occurrence Handle1:STN:280:CSuD387mtlw%3D Occurrence Handle4355998

    CAS  PubMed  Google Scholar 

  14. 14

    P. Lijnen V. Petrov (2000) ArticleTitleInduction of cardiac fibrosis by aldosterone. J. Mol. Cell Cardiol. 32 865–879 Occurrence Handle10.1006/jmcc.2000.1129 Occurrence Handle1:CAS:528:DC%2BD3cXkvVOrsr0%3D Occurrence Handle10888242

    Article  CAS  PubMed  Google Scholar 

  15. 15

    M. Lombes M.E. Oblin J.M. Gasc E.E. Baulieu N. Farman J.P. Bonvalet (1992) ArticleTitleImmunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor. Circ. Res. 71 503–510 Occurrence Handle1:CAS:528:DyaK38Xls1Cis7k%3D Occurrence Handle1323429

    CAS  PubMed  Google Scholar 

  16. 16

    W.J., II Meyer N.R. Nichols (1981) ArticleTitleMineralocorticoid binding in cultured smooth muscle cells and fibroblasts from rat aorta. J. Steroid Biochem. 14 1157–1168 Occurrence Handle10.1016/0022-4731(81)90046-7 Occurrence Handle1:CAS:528:DyaL38XhtlKisb8%3D Occurrence Handle6273655

    Article  CAS  PubMed  Google Scholar 

  17. 17

    G. Miric C. Dallemagne Z. Endre S. Margolin S.M. Taylor L. Brown (2001) ArticleTitleReversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br. J. Pharmacol. 133 687–694 Occurrence Handle1:CAS:528:DC%2BD3MXlsVCrtLg%3D Occurrence Handle11429393

    CAS  PubMed  Google Scholar 

  18. 18

    J. Nielsen T.H. Kwon S. Masilamani K. Beutler H. Hager S. Nielsen M.A. Knepper (2002) ArticleTitleSodium transporter abundance profiling in kidney: effect of spironolactone. Am. J. Physiol. 283 F923–F933

    Google Scholar 

  19. 19

    H. Oberleithner J. Reinhardt H. Schillers P. Pagel S.W. Schneider (2000) ArticleTitleAldosterone and nuclear volume cycling. Cell Physiol. Biochem. 10 429–434 Occurrence Handle10.1159/000016379 Occurrence Handle1:CAS:528:DC%2BD3MXjt1aks7g%3D Occurrence Handle11125225

    Article  CAS  PubMed  Google Scholar 

  20. 20

    H. Oberleithner M. Weigt H.-J. Westphale W. Wang (1987) ArticleTitleAldosterone activates Na+/H+ exchange and raises cytoplasmic pH in target cells of the amphibian kidney. Proc. Natl. Acad. Sci. USA 84 1464–1468 Occurrence Handle1:CAS:528:DyaL2sXhsV2ku70%3D Occurrence Handle3029782

    CAS  PubMed  Google Scholar 

  21. 21

    J.A. Oliver Q. Al Awqati (1998) ArticleTitleAn endothelial growth factor involved in rat renal development. J. Clin. Invest. 102 1208–1219 Occurrence Handle1:CAS:528:DyaK1cXmtFyhsbo%3D Occurrence Handle9739055

    CAS  PubMed  Google Scholar 

  22. 22

    E.A. Palmieri B. Biondi S. Fazio (2002) ArticleTitleAldosterone receptor blockade in the management of heart failure. Heart Fail. Rev. 7 205–219 Occurrence Handle10.1023/A:1015336831407 Occurrence Handle1:CAS:528:DC%2BD38XkvVWqurg%3D Occurrence Handle11988643

    Article  CAS  PubMed  Google Scholar 

  23. 23

    S. Rajagopalan D. Duquaine S. King B. Pitt P. Patel (2002) ArticleTitleMineralocorticoid receptor antagonism in experimental atherosclerosis. Circulation 105 2212–2216 Occurrence Handle10.1161/01.CIR.0000015854.60710.10 Occurrence Handle1:CAS:528:DC%2BD38XktlOku7Y%3D Occurrence Handle11994257

    Article  CAS  PubMed  Google Scholar 

  24. 24

    B.C. Rossier (2002) ArticleTitleHormonal regulation of the epithelial sodium channel ENaC: N or P(o)? J. Gen. Physiol. 120 67–70 Occurrence Handle10.1085/jgp.20028638 Occurrence Handle1:CAS:528:DC%2BD38XlslOhsLk%3D Occurrence Handle12084776

    Article  CAS  PubMed  Google Scholar 

  25. 25

    C. Schafer V. Shahin L. Albermann M.J. Hug J. Reinhardt H. Schillers S.W. Schneider H. Oberleithner (2002) ArticleTitleAldosterone signaling pathway across the nuclear envelope. Proc. Natl. Acad. Sci. USA 99 7154–7159 Occurrence Handle10.1073/pnas.092140799 Occurrence Handle1:CAS:528:DC%2BD38XjvFCqu7s%3D Occurrence Handle11983859

    Article  CAS  PubMed  Google Scholar 

  26. 26

    M. Schneider A. Ulsenheimer M. Christ M. Wehling (1997a) ArticleTitleNongenomic effects of aldosterone on intracellular calcium in porcine endothelial cells. Am. J. Physiol 272 E616–E620 Occurrence Handle1:CAS:528:DyaK2sXjt1Kqt7c%3D

    CAS  Google Scholar 

  27. 27

    S.W. Schneider Y. Yano B.E. Sumpio B.P. Jena J.P. Geibel M. Gekle H. Oberleithner (1997b) ArticleTitleRapid aldosterone-induced cell volume increase of endothelial cells measured by the atomic force microscope. Cell Biol. Int. 21 759–768 Occurrence Handle1:CAS:528:DyaK1cXmslCgurk%3D

    CAS  Google Scholar 

  28. 28

    J.S. Silvestre V. Robert C. Heymes B. Aupetit-Faisant C. Mouas J.M. Moalic B. Swynghedauw C. Delcayre (1998) ArticleTitleMyocardial production of aldosterone and corticosterone in the rat. Physiological regulation. J. Biol. Chem. 273 4883–4891 Occurrence Handle10.1074/jbc.273.9.4883 Occurrence Handle1:CAS:528:DyaK1cXhs1Cgtbw%3D Occurrence Handle9478930

    Article  CAS  PubMed  Google Scholar 

  29. 29

    C.T. Stier Jr P.N. Chander R. Rocha (2002) ArticleTitleAldosterone as a mediator in cardiovascular injury. Cardiol. Rev. 10 97–107 Occurrence Handle10.1097/00045415-200203000-00008 Occurrence Handle11895576

    Article  PubMed  Google Scholar 

  30. 30

    J.B. Stokes (1999) ArticleTitleDisorders of the epithelial sodium channel: insights into the regulation of extracellular volume and blood pressure. Kidney Int. 56 2318–2333 Occurrence Handle10.1046/j.1523-1755.1999.00803.x Occurrence Handle1:CAS:528:DC%2BD3cXisVCgsw%3D%3D Occurrence Handle10594813

    Article  CAS  PubMed  Google Scholar 

  31. 31

    J.D. Symons S. Schaefer (2001) ArticleTitleNa(+)/H(+) exchange subtype 1 inhibition reduces endothelial dysfunction in vessels from stunned myocardium. Am. J. Physiol. 281 H1575–H1582 Occurrence Handle1:CAS:528:DC%2BD3MXnsVyqtLo%3D

    CAS  Google Scholar 

  32. 32

    Y. Takeda I. Miyamori T. Yoneda K. Iki H. Hatakeyama I.A. Blair F.Y. Hsieh R. Takeda (1995) ArticleTitleProduction of aldosterone in isolated rat blood vessels. Hypertension 25 170–173 Occurrence Handle1:CAS:528:DyaK2MXkvF2gt7w%3D Occurrence Handle7843766

    CAS  PubMed  Google Scholar 

  33. 33

    Y. Takeda T. Yoneda M. Demura I. Miyamori H. Mabuchi (2000) ArticleTitleSodium-induced cardiac aldosterone synthesis causes cardiac hypertrophy. Endocrinology 141 1901–1904 Occurrence Handle1:CAS:528:DC%2BD3cXlt1Wnsbs%3D Occurrence Handle10803602

    CAS  PubMed  Google Scholar 

  34. 34

    K.T. Weber C.G. Brilla (1991) ArticleTitlePathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 83 1849–1865 Occurrence Handle1:STN:280:By6B2cbkt1A%3D Occurrence Handle1828192

    CAS  PubMed  Google Scholar 

  35. 35

    M. Wehling J. Kasmayr K. Theisen (1989) ArticleTitleFast effects of aldosterone on electrolytes in human lymphocytes are mediated by the sodium-proton-exchanger of the cell membrane. Biochem. Biophys. Res. Commun. 164 961–967 Occurrence Handle1:CAS:528:DyaK3cXptVE%3D Occurrence Handle2556129

    CAS  PubMed  Google Scholar 

Download references


We thank Mrs. Marianne Wilhelmi and Hannelore Arnold for their excellent HUVEC culture work. We thank Drs. Kleemann and Lang (Aventis Pharma GmbH, Deutschland) for kindly providing cariporide. The study was supported by IZKF Münster (Project A9) and the Volkswagenstiftung (Project BD 151103).

Author information



Corresponding author

Correspondence to H. Oberleithner.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Oberleithner, H., Schneider, S., Albermann, L. et al. Endothelial Cell Swelling by Aldosterone . J. Membrane Biol. 196, 163–172 (2003). https://doi.org/10.1007/s00239-003-0635-6

Download citation


  • HUVECs
  • Atomic force microscopy
  • Cariporide
  • Mineralocorticoids
  • Na+ channel
  • Vasculopathies