, Volume 14, Issue 3, pp 277–284

Role of endothelin in diabetic vascular complications



Endothelin-1 (ET-1), a 21 amino acid peptide originally purified from conditioned medium of cultures of porcine aortic endothelial cells, is recognized as a product of many other cells as well. It is now known that there are three endothelin genes in the human genome (ET-1, ET-2, and ET-3). ET-1 and ET-2 are both strong vasoconstrictors, whereas ET-3 is a potentially weaker vasoconstrictor than the other two isoforms. Besides being the most potent vasoconstrictor yet known, ET-1 also acts as a mitogen on the vascular smooth muscle, and, thus, it may play a role in the development of vascular diseases. It is well known that accelerated angiopathy is a major complication in diabetes mellitus. As generalized endothelial cell damage is thought to occur in diabetic patients, ET-1, being released from the damaged endothelial cells, is able to make contact with the underlying vascular smooth muscle cells and thus could be one important cause of diabetic angiopathy. This article summarizes the reported literature of the role of ET-1 in the development of diabetic complications, with particular focus on the possible role of Et-1 in mediating the effects of angiotensin-converting enzyme inhibitors.

Key Words

Endothelin diabetic vascular complications ACE inhibitors 


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  1. 1.
    Yanagisawa, M., Kurihara, H., Kimura, S., Tomobe, Y., Kobayashi, M., and Mitsui, Y. (1988). Nature 332, 411–415.PubMedCrossRefGoogle Scholar
  2. 2.
    Inoue, A., Yanagisawa, M., Kimura, S., Kasuya, Y., Miyauchi, T., Goto, K., and Masaki, T. (1989). Proc. Natl. Acad. Sci. USA 86, 2863–2867.PubMedCrossRefGoogle Scholar
  3. 3.
    Takahashi, M., Matsushita, Y., Ijima, Y., and Tanzawa, K. (1993). J. Biol. Chem. 268, 21,394–21,398.Google Scholar
  4. 4.
    Emoto, N. and Yanagisawa, M. (1995). J. Biol. Chem. 270, 15,262–15,268.Google Scholar
  5. 5.
    Shimada, K., Takahashi, M., Ikeda, M., and Tanzawa, K. (1995). FEBS Lett. 371, 140–144.PubMedCrossRefGoogle Scholar
  6. 6.
    Valdenaire, O., Rohrbacher, E., and Mattei, M. G. (1995). J. Biol. Chem. 270, 29,794–29,798.Google Scholar
  7. 7.
    Schweizer, A., Valdenaire, O., Nelbock, P., et al. (1997). Biochem. chem. J. 328, 871–877.Google Scholar
  8. 8.
    Valdenaire, O., Lepailleur-Enouf, D., Egidy, G., et al. (1999). Eur. J. Biochem. 264, 341–349.PubMedCrossRefGoogle Scholar
  9. 9.
    Masaki, T. (1993). Endocr. Rev. 14, 256–268.PubMedCrossRefGoogle Scholar
  10. 10.
    Takahashi, K., Jones, P. M., Kanse, S. M, et al. (1990). Gastroenterology 99, 1660–1667.PubMedGoogle Scholar
  11. 11.
    Takahashi, K., Ghatei, M. A., Jones, P. M., et al. (1991). J. Clin. Endocrinol. Metab. 72, 693–699.PubMedGoogle Scholar
  12. 12.
    Takahashi, K., Ghatei, M. A., Jones, P. M., et al. (1991). J. Cardiovasc. Pharmacol. 17(Suppl. 7), S101-S103.PubMedCrossRefGoogle Scholar
  13. 13.
    Arai, H., Hori, S., Aramori, I., Ohkubo, H., and Nakanishi, S. (1990). Nature 348, 730–732.PubMedCrossRefGoogle Scholar
  14. 14.
    Sakurai, T., Yanagisawa, M., Takuwa, Y., et al. (1990). Nature 348, 732–735.PubMedCrossRefGoogle Scholar
  15. 15.
    Karne, S., Jayawickreme, C. K., and Lerner, M. R. (1993). J. Biol. Chem. 268, 19,126–19,133.Google Scholar
  16. 16.
    Moreland, S., McMullen, D. M., Delaney, C. L., Lee, V. G., and Hunt, J. T. (1992). Biochem. Biophys. Res. Commun. 184, 100–106.PubMedCrossRefGoogle Scholar
  17. 17.
    Iwasaki, S., Homma, T., Matsuda, Y., and Kon, V. (1995). J. Biol. Chem. 270, 6997–7003.PubMedCrossRefGoogle Scholar
  18. 18.
    Lam, H. C., Lee, J. K., and Lai, K. H. (2000). Endocrine 12, 77–80.PubMedCrossRefGoogle Scholar
  19. 19.
    McMillen, M. A. and Sumpio, B. E. (1995). J. Am. Coll. surg. 180, 621–637.PubMedGoogle Scholar
  20. 20.
    McMillan, D. E. (1984). Microcirc. Endothel. Lymphat. 1, 3–24.Google Scholar
  21. 21.
    Rubanyi, G. M. and Botelho, L. H. (1991). FASEB J. 5, 2713–2720.PubMedGoogle Scholar
  22. 22.
    Nugent, A. G., McGurk, C., Hayes, J. R., and Johnstone, C. D. (1996). Diabetes 45, 105–107.PubMedCrossRefGoogle Scholar
  23. 23.
    Sármán, B., Tóth, M., and Somogyi, A. (1998). Diabetes Metab. Rev. 14, 171–175.PubMedCrossRefGoogle Scholar
  24. 24.
    Rohner, E. M. (1993). BMJ 307, 1195–1199.Google Scholar
  25. 25.
    Riva, C. E. and Loebl, M. (1977). Invest. Ophthalmol. 16, 586–592.Google Scholar
  26. 26.
    Chakravarthy, U. and Archer, D. B. (1992). Br. J. Ophthalmol. 76, 107, 108.PubMedGoogle Scholar
  27. 27.
    Ye, X., Laties, A. M., and Stone, R. A. (1990). Invest. Ophthalmol. 31, 1731–1737.Google Scholar
  28. 28.
    Cogan, D. G., Toussaint, D., and Kuwabara, T. (1961). Arch. Ophthalmol. 63, 366–368.Google Scholar
  29. 29.
    Herman, I. M. and D'Amore, P. A. (1985). J. Cell Biol. 101, 43–52.PubMedCrossRefGoogle Scholar
  30. 30.
    Takahashi, K., Brooks, R. A., Kanse, S. M., Ghatei, M. A., Kohner, E. M., and Bloom, S. R. (1989). Diabetes 38, 1200–1202.PubMedCrossRefGoogle Scholar
  31. 31.
    Nyborg, N. C. B., Pieto, D., Benedito, S., and Nielsen, P. J. (1991). Invest. Ophthalmol. Vis. Sci. 32, 27–31.PubMedGoogle Scholar
  32. 32.
    Chakravarthy, U., Gardiner, T. A., Anderson, P., Archer, D. B., and Trimble, E. R. (1992). Microvasc. Res. 43, 241–254.PubMedCrossRefGoogle Scholar
  33. 33.
    Ogata, M., Naruse, M., Iwasaki, N., et al. (1998). J. Cardiovasc. Pharmacol. 31(Suppl. 1), S378,S379.CrossRefGoogle Scholar
  34. 34.
    Temple, R. C., Carrington, C. A., Luzio, S. D., Owens, D. R., Schneider, A. E., and Sobey, W. J. (1989). Lancet 1, 293–295.PubMedCrossRefGoogle Scholar
  35. 35.
    Hattori, Y., Kasai, K., Nakamura, T., Emoto, T., and Shimoda, S. (1991). Metabolism 40, 165–169.PubMedCrossRefGoogle Scholar
  36. 36.
    Ferri, C. and De-Mattia, G. (1995). Metabolism 44, 689, 690.PubMedCrossRefGoogle Scholar
  37. 37.
    Metsärinne, K., Saijonomaa, O., Yki-Järvinen, H., and Fyhrquist, F. (1994). Metabolism 43, 878–882.PubMedCrossRefGoogle Scholar
  38. 38.
    Yamauchi, T., Ohnaka, K., Takayanagi, R., Umeda, F., and Nawata, H. (1990). FEBS Lett. 267, 16–18.PubMedCrossRefGoogle Scholar
  39. 39.
    Wolpert, H. A., Steen, S. N., Istfan, N. W., and Simonson, D. C. (1993). Metabolism 42, 1027–1030.PubMedCrossRefGoogle Scholar
  40. 40.
    Ferri, C., Carlomagno, A., Coassin, S., Baldoncini, R., and Cassone-Faldetta, M. R. (1995). Diabetes Care 18, 226–233.PubMedCrossRefGoogle Scholar
  41. 41.
    Ferri, C., Laurenti, O., Bellini, C., et al. (1995). Am. J. Hypertens. 8, 40–71.PubMedCrossRefGoogle Scholar
  42. 42.
    Frank, H. J. L., Levin, E. R., Pedram, A. (1993). Endocrinology 133, 1092–1097.PubMedCrossRefGoogle Scholar
  43. 43.
    Takahashi, K., Suda, K., Lam, H. C., Ghatei, M. A., and Bloom, S. R. (1991). J. Endocrinol. 130, 123–127.PubMedGoogle Scholar
  44. 44.
    De la Rubia, G., Oliver, F. J., Inoguchi, T., and King, G. L. (1992). Diabetes 41, 1533–1539.PubMedCrossRefGoogle Scholar
  45. 45.
    Bursell, S. E., Clermont, A. C., Oren, B., and King, G. L. (1995). Invest. Ophthalmol. Vis. Sci. 36, 596–607.PubMedGoogle Scholar
  46. 46.
    Chakrabarti, S., Gan, X. T., Merry, A., Karmazyn, M., and Sima, A. A. (1998). Curr. Eye Res. 17, 301–307.PubMedCrossRefGoogle Scholar
  47. 47.
    Chakrabarti, S. and Sima, A. A. (1997). Diabetes Res. Clin. Pract. 37, 109–120.PubMedCrossRefGoogle Scholar
  48. 48.
    Chakrabarthy, U., Hayes, R. G., Stitt, A. W., and Douglas, A. (1997). Invest. Ophthalmol. Vis. Sci. 38, 2144–2151.Google Scholar
  49. 49.
    Takagi, C., Bursell, S. E., Lin, Y. W., et al. (1996). Invest. Ophthalmol. Vis. Sci. 37, 2504–2518.PubMedGoogle Scholar
  50. 50.
    Mogensen, C. E., Østerby, R., and Gundersen, H. J. G. (1979). Diabetologia 17, 71–76.PubMedCrossRefGoogle Scholar
  51. 51.
    Vora, J. P., Dolben, J., Dean J. D., et al. (1992). Kidney Int. 41, 829–835.PubMedCrossRefGoogle Scholar
  52. 52.
    Lam, H. C., Lee, J. K., Chiang, H. T., et al. (1995). J. Cardiovasc. Pharmacol. 26(Suppl. 3), S479-S481.PubMedGoogle Scholar
  53. 53.
    De-Mattia, G., Cassone-Faldetta, M., Bellini, C., et al. (1998). Am. J. Hypertens. 11, 983–988.PubMedCrossRefGoogle Scholar
  54. 54.
    Shin, S. J., Lee, Y. J., Lin, S. R., Tan, M. S., Lai, Y. H., and Tsai, J. H. (1995). Nephron 70, 486–493.PubMedGoogle Scholar
  55. 55.
    Awazu, M., Parker, R. E., Harvie, B. R., Ichikawa, I., and Kon, V. (1991). J. Cardiovasc. Pharmacol. 17(Suppl. 7), S500-S502.PubMedCrossRefGoogle Scholar
  56. 56.
    Hurst, R. D., Stevanovic, Z. S., Munk, S., et al. (1995). Diabetes 44, 759–766.PubMedCrossRefGoogle Scholar
  57. 57.
    Anderson, S. and Brenner, B. M. (1988). Diabetes Metab. Rev. 4, 163–177.PubMedCrossRefGoogle Scholar
  58. 58.
    Lee, Y. J., Shin, S. J., and Tsai, J. H. (1994). Diabetes Care 17, 253–266.Google Scholar
  59. 59.
    Orisio, S., Benigni, A., Bruzzi, I., et al. (1993). Kidney Int. 43, 354–358.PubMedCrossRefGoogle Scholar
  60. 60.
    Zoccali, C., Leonardis, D., Parlongo, S., Mallamaci, F., and Postorino, M. (1995). Nephrol. Dial. Transplant 10, 1320–1323.PubMedGoogle Scholar
  61. 61.
    Simonson, M. S., Wann, S., Mene, P., et al. (1989). J. Clin. Invest. 83, 708–712.PubMedCrossRefGoogle Scholar
  62. 62.
    Ishimura, E., Shouji, S., Nishizawa, Y., Morii, H., and Kashgarian, M. (1991). J. Am. Soc. Nephrol. 2, 546.Google Scholar
  63. 63.
    Nayer, W. G. (1990). Endothelin and the kidney. In: The Endothelins. Nayer, W. G. (ed.). Springer-Verlag: Berlin.Google Scholar
  64. 64.
    Dyck, P. J. (1989). Neurology 39, 111–118.PubMedGoogle Scholar
  65. 65.
    Cameron, N. E., Cotter, M. A., and Low, P. A. (1991). Am. J. Physiol. 261, E1-E8.PubMedGoogle Scholar
  66. 66.
    Tuck, R. R., Schmelzer, J. D., and Low, P. A. (1984). Brain 107, 935–950.PubMedCrossRefGoogle Scholar
  67. 67.
    Pugliese, G., Tilton, R. G., Speedy, A., et al. (1989). Diabetologia 32, 845–857.PubMedCrossRefGoogle Scholar
  68. 68.
    Zochodne, D. W. and Ho, L. T. (1992). Can. J. Physiol. Pharmacol. 70, 651–659.PubMedGoogle Scholar
  69. 69.
    Zochodne, D. W., Ho, L. T., and Allison, J. A. (1994). J. Neurol. Sci. 127, 36–42.PubMedCrossRefGoogle Scholar
  70. 70.
    Nukada, H. (1986). Diabetes 35, 1058–1061.PubMedCrossRefGoogle Scholar
  71. 71.
    Nukada, H. (1992). Muscle Nerve 15, 1116–1122.PubMedCrossRefGoogle Scholar
  72. 72.
    Kihara, M. and Low, P. A. (1995). Exp. Neurol. 132, 180–185.PubMedCrossRefGoogle Scholar
  73. 73.
    Zochodne, D. W., Ho, L. T., and Gross, P. M. (1992). Am. J. Physiol. 263, H1806-H1810.PubMedGoogle Scholar
  74. 74.
    Zochodne, D. W., Cheng, C. and Sun, H. (1996). Diabetes 45, 627–632.PubMedCrossRefGoogle Scholar
  75. 75.
    Lam, H. C., Takahashi, K., Ghatei, M. A., Warrens, A. N., Rees, A. J., and Bloom, S. R. (1991). J. Cardiovasc. Pharmacol. 17(Suppl. 7), S390-S393.PubMedCrossRefGoogle Scholar
  76. 76.
    Cameron, N. E. and Cotter, M. A. (1996). J. Pharmacol. Exp. Ther. 278, 1262–1268.PubMedGoogle Scholar
  77. 77.
    Cameron, N. E., Dines, K. C., and Cotter, M. A. (1994). Diabetologia 37, 1209–1215.PubMedGoogle Scholar
  78. 78.
    Bassirat, M. and Khalil, Z. (2000). Microvasc. Res. 59, 88–98.PubMedCrossRefGoogle Scholar
  79. 79.
    Stevens, E. J. and Tomlinson, D. R. (1995). Br. J. Pharmacol. 115, 373–379.PubMedGoogle Scholar
  80. 80.
    Francavilla, S., Properzi, G., Bellini, C., Marino, G., Ferri, C., and Santucci, A. (1997). J. Urol. 158, 1770–1774.PubMedCrossRefGoogle Scholar
  81. 81.
    Saenz de Tejada, I., Carson, M. P., De Las Morenas, A., Goldstein, I., and Traish, A. M. (1991). Am. J. Physiol. 261, H1078-H1085.PubMedGoogle Scholar
  82. 82.
    Takahashi, K., Ghatei, M. A., Lam, H. C., O'Halloram, D. J., and Bloom, S. R. (1990). Diabetologia 33, 306–310.PubMedCrossRefGoogle Scholar
  83. 83.
    Morise, T., Takeuchi, Y., Kawano, M., Koni, I., and Takeda, R. (1995). Diabetes Care 18, 87–89.PubMedCrossRefGoogle Scholar
  84. 84.
    Kawamura, M., Ohgawara, H., Naruse, M., et al. (1992). Diabetes Care 15, 1396,1397.PubMedCrossRefGoogle Scholar
  85. 85.
    Donatelli, M., Colletti, I., Bucalo, M. L., Russo, V., and Verga, S. (1994) Diabetes Res. 25, 159–164.PubMedGoogle Scholar
  86. 86.
    Letizia, C., Iannaccone, A., Cerci, S., et al. (1997). Horm. Metab. Res. 29, 247–251.PubMedGoogle Scholar
  87. 87.
    Laurenti, O., Vingolo, E. M., Desideri, G. B., et al. (1997). Exp. Clin. Endocrinol. Diabetes 105(Suppl. 2), 40–42.PubMedCrossRefGoogle Scholar
  88. 88.
    Haak, T., Jungmann, E., Felber, A., Hillmann, U., and Usadel, K. H. (1992). Am. J. Hypertens. 5, 161–166.PubMedGoogle Scholar
  89. 89.
    Bertello, P., Veglio, F., Pinna, G., Guridi, L., Molino, P., Albano, S., and Chiandussi, L. (1994). Diabetes Care 17, 574–577.PubMedCrossRefGoogle Scholar
  90. 90.
    Kamoi, K., Ishibashi, M., and Yamaji, T. (1994). Diabetes Res. Clin. Pract. 24, 125–129.PubMedCrossRefGoogle Scholar
  91. 91.
    Tsunoda, K., Abe, K., Sato, T., Yokosawa, S., and Yoshinaga, K. (1991). Clin. Exp. Pharmacol. Physiol. 18, 731,732.PubMedGoogle Scholar
  92. 92.
    Hoffman, A., Grossman, E., and Keiser, H. R. (1990) Eur. J. Pharmacol. 182, 603–606.PubMedCrossRefGoogle Scholar
  93. 93.
    Teuscher, A., Schnell, H., and Wilson, P. W. F. (1988). Diabetes Care 11, 246–251.PubMedCrossRefGoogle Scholar
  94. 94.
    Tolins, J. P. and Raij, L. (1989). Am. J. Med. 87 (Suppl. 6A), 29S-33S.PubMedCrossRefGoogle Scholar
  95. 95.
    Kasiske, B. L., Kalil, R. S. N., Ma, J. Z., Liao, M., and Keane, W. F. (1993). Ann. Intern. Med. 118, 129–138.PubMedGoogle Scholar
  96. 96.
    Marre, M., Chatellier, G., Leblanc, H., Guyene, T. T., Menard, J., and Passa, P. (1988). BMJ 297, 1092–1095.PubMedGoogle Scholar
  97. 97.
    Mathiesen, E. R., Hommel, E., Giese, J., and Parving, H. H. (1991). BMJ 303, 81–87.PubMedCrossRefGoogle Scholar
  98. 98.
    Chaturvedi, N., Sjolie, A. K., Stephenson, J. M., et al. (1998). Lancet 351, 28–31.PubMedCrossRefGoogle Scholar
  99. 99.
    Yoshida, H. and Nakamura, M. (1992). Life Sci. 50, 195–200.CrossRefGoogle Scholar
  100. 100.
    Lam, H. C., Lee, J. K., Koh, S. J., and Chiang, H. T. (1996). Acute effect of captopril on urinary excretion of endothelin in normal Chinese subjects. In: Adrenal glands, vascular system and hypertension. Vinson G. P. and Anderson, D. C. (eds.). Journal of Endocrinology Ltd: Bristol, pp. 253–257.Google Scholar
  101. 101.
    Ferri, C., Laurenti, O., Bellini, C., et al. (1995). Am. J. Hypertens. 8, 40–47.PubMedCrossRefGoogle Scholar
  102. 102.
    Lam, H. C., Lee, J. K., Chiang, H. T., Chuang, M. J., and Wang, M. C. (1998). J. Cardiovasc. Pharmacol. 31(Suppl. 1), S496-S500.PubMedCrossRefGoogle Scholar
  103. 103.
    Fukui, M., Nakamura, T., Ebihara, I., et al. (1994). J. Lab. Clin. Med. 123, 763–768.PubMedGoogle Scholar
  104. 104.
    Hocher, B., Lun, A., Priem, F., Neumayer, H. H., and Raschack, M. (1998). J. Cardiovasc. Pharmacol. 31(Suppl. 1), S492-S495.PubMedCrossRefGoogle Scholar
  105. 105.
    Coutinho, M., Gerstein, H. C., Wang, Y., and Yusuf, S. (1999). Diabetes Care 22, 233–240.PubMedCrossRefGoogle Scholar
  106. 106.
    Townend, J., Doran, J., Jones, S., and Davies, M. (1994). Int. J. Cardiol. 43, 299–304.PubMedCrossRefGoogle Scholar
  107. 107.
    Grenier, O., Pousset, F., Isnard, R., et al. (1996). Cardiovasc. Drugs Ther. 10, 561–565.PubMedCrossRefGoogle Scholar
  108. 108.
    Galatius-Jensen, S., Wroblewski, H., Emmeluth, C., Bie, P., Haunso, S., and Kastrup, J. (1996). Cardiovasc. Res. 32, 1148–1154.PubMedCrossRefGoogle Scholar
  109. 109.
    Lerman, A., Hildebrand, F. L., Aarhus, L. L., and Burnett, J. C. (1991). Circulation 83, 1804–1814.Google Scholar
  110. 110.
    Monge, J. C. (1998). J. Cardiovasc. Pharmacol. 32(Suppl. 2), S36-S42.PubMedGoogle Scholar

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© Humana Press Inc. 2004

Authors and Affiliations

  1. 1.Division of Endocrinology and Metabolism, Department of MedicineVeterans General Hospital-Kaohsiung and National Yang-Ming University School of MedicineKaohsiungTaiwan, Republic of China

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