Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Influence of hypoxia on hepatic and renal endothelin gene expression


This study aimed to investigate the influence of different forms of tissue hypoxia on the expression of the endothelin genes in kidneys and livers. Tissue hypoxia in rats was induced by five different manoeuvres, namely hypoxia (8% O2), functional anaemia (0.1 % CO), haemorrhage (haematocrit, hct = 0.12), cobalt treatment (60 mg/kg) for 6 h each and renal artery stenosis (0.2-mm clips) for 2 days. Endothelin-1 (ET-1) mRNA levels in the kidneys were increased by 200% with renal artery stenosis, 70% by hypoxia, 50% by anaemia, 30% by CO, but were not changed by cobalt. ET-3 mRNA in the kidneys decreased during renal artery clipping and cobalt treatment and were not significantly changed under the other conditions. ET2 mRNA was not detected in the kidneys and livers. The abundance of ET-1 in the livers of normoxic animals was about 15% of that found in the kidney. Hypoxia increased ET-1 mRNA by 200%, haemorrhage by 400%, whilst CO and cobalt did not change hepatic ET-1 gene expression. The abundance of ET-3 mRNA in the livers of normoxic animals was about 6% of that found in the kidneys. The expression of the ET-3 gene in the livers was decreased by CO, but was not changed by any of the other experimental conditions used. These findings suggest that hypoxaemia and tissue hypoxia are moderate stimuli for the expression of the ET-1 gene but not for the ET-3 gene in the kidney and more potent stimuli in the liver, whilst cobalt does not activate ET-1 gene expression in the kidneys nor the livers.

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


  1. 1.

    Bachmann S, LeHir M, Eckardt K-U (1993) Co-localization of erythropoietin mRNA and ecto-5′-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin. J Histochem Cytochem 41:335–341

  2. 2.

    Beru N, McDonald J, Lacombe C, Goldwasser E (1986) Expression of erythropoietin gene. Mol Cell Biol 6:2571–2575

  3. 3.

    Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159

  4. 4.

    Cristol JP, Warner TD, Thiemermann C, Vane JR (1993) Mediation via different receptors of the vasoconstrictor effects of endothelins and sarafotoxins in the systemic circulation and renal vasculature of the anaesthetized rat. Br J Pharmacol 108:776–779

  5. 5.

    Eckardt K-U, Ratcliffe PJ, Tan CC, Bauer C, Kurtz A (1992) Age dependent expression of the erythropoietin gene in rat liver and kidneys. J Clin Invest 89:753–760

  6. 6.

    Eckardt K-U, Pugh W, Ratcliffe PJ, Kurtz A (1993) Oxygendependent modulation of the erythropoietin mRNA in rat hepatocytes in vitro. Pflügers Arch 423:356–364

  7. 7.

    Elton ST, Oparil S, Taylor GR, Hicks PH, Yang RH, Jin H, Chen YF (1992) Normobaric hypoxia stimulates endothelin-1 gene expression in the rat. Am J Physiol 263:R1260-R1264

  8. 8.

    Falanga V, Qian SW, Danielpour D, Katz MH, Roberts AB, Sporn MB (1991) Hypoxia upregulates the synthesis of TGFbeta 1 by human dermal fibroblasts. J Invest Dermatol 97: 634–637

  9. 9.

    Firth JD, Ratcliffe PJ (1992) Organ distribution of the three rat endothelin messenger RNAs and the effects of ischemia on renal gene expression. J Clin Invest 90: 1023–1031

  10. 10.

    Gandhi CR, Stephenson K, Olson MS (1990) Endothelin, a potent peptide agonist in the liver. J Biol Chem 265:17432–17435

  11. 11.

    Gertler JP, Ocasio VH (1993) Endothelin production by hypoxic human endothelium. J Vase Surg 18:178–184

  12. 12.

    Goldberg MA, Dunning SP, Bunn HF (1988) Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein. Science 242:1412–1415

  13. 13.

    Hirata Y, Takagi Y, Fukuda Y, Marumo F (1989) Endothelin is a potent mitogen for rat vascular smooth muscle cells. Atherosclerosis 78:225–228

  14. 14.

    Holmer S, Rinne B, Eckardt K-U, Le Hir M, Schricker K, Kaissling B, Riegger G, Kurtz A (1994) Role of renal nerves for the expression of renin in adult rat kidney. Am J Physiol 266:F738-F745

  15. 15.

    Jelkmann W (1992) Erythropoietin: structure, control of production, and function. Physiol Rev 72:449–489

  16. 16.

    Kagamu H, Suzuki T, Arakawa M, Mitsui Y (1994) Low oxygen enhances endothelin-1 (ET-1) production and responsiveness to ET-1 in cultured cardiac myocytes. Biochem Biophys Res Commun 202:1612–1618

  17. 17.

    Kourembanas S, Hannan RL, Faller DV (1990) Oxygen tension regulates the expression of the platelet-derived growth factor-B chain gene in human endothelial cells. J Clin Invest 86:670–674

  18. 18.

    Kourembanas S, Marsden PA, McQuillan LP, Faller DV (1991) Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. J Clin Invest 88:1054–1057

  19. 19.

    Le Hir M, Eckardt K-U, Kaissling B, Koury ST, Kurtz A (1991) Structure-function correlations in erythropoietin formation and oxygen sensing in the kidney. Klin Wochenschr 69:567–575

  20. 20.

    Li H, Elton S, Chen YF, Oparil S (1994) Increased endothelin receptor gene expression in hypoxic rat lung. Am J Physiol 266:L553-L560

  21. 21.

    MacCumber MW, Ross CA, Glaser BM, Snyder SH (1989) Endothelin: visualisation of mRNAs by in situ hybridization provides evidence for local action. Proc Natl Acad Sci USA 86:7285–7289

  22. 22.

    Miller WL, Redfield MM, Burnett JC (1989) Integrated cardiac, renal, and endocrine actions of endothelin. J Clin Invest 83:317–320

  23. 23.

    Nir A, Clavell AL, Heublein D, Aarhus LL, Burnett JC (1994) Acute hypoxia and endogenous renal endothelin. J Am Soc Nephrol 4:1920–1924

  24. 24.

    Pupilli C, Brunori M, Misciglia N, Selli C, Ianni L, Yanagisawa M, Mannelli M, Serio M (1994) Presence and distribution of endothelin-1 gene expression in human kidney. Am J Physiol 267:F679-F687

  25. 25.

    Ratcliffe PJ, Jones RW, Philipps RE, Nicholls LG, Bell JI (1990) Oxygen-dependent modulation of erythropoietin mRNA levels. J Exp Med 172:657–660

  26. 26.

    Schuster SJ, Badiavas EV, Costa-Giomi P, Weinmann R, Erstev AJ, Caro J (1989) Stimulation of EPO gene transcription during hypoxia and cobalt exposure. Blood 73:13–16

  27. 27.

    Shweiki D, Itin A, Soffer D, Keshet E (1992) Vascular endothelial growth factor induced by hypoxia may mediate hypoxiainitiated angiogenesis. Nature 359:843–945

  28. 28.

    Simonson MS, Wann S, Mene P, Dubyak GR, Kester M, Nakazato Y, Sedor JR, Dunn MJ (1989) Endothelin stimulates phospholipase C, Na+/H+ exchange, c-fos expression and mitogenesis in rat mesangial cells. J Clin Invest 83:708–712

  29. 29.

    Tan CC, Eckardt K-U, Firth JD, Ratcliffe PJ (1992) Feedback modulation of renal and hepatic erythropoietin mRNA in response to graded anemia and hypoxia. Am J Physiol 263:F474-F481

  30. 30.

    Wiebke JL, Montrose-Rafizadeh C, Zeitlin PL, Guggino WB (1992) Effect of hypoxia on endothelin-1 production by pulmonary vascular endothelial cells. Biochim Biophys Acta 1134:105–111

  31. 31.

    Yanagisawa M, Masaki T (1989) Endothelin, a novel endothelium-derived peptide. Biochem Pharmacol 38:1877–1883

  32. 32.

    Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415

Download references

Author information

Correspondence to Theresia Ritthaler.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ritthaler, T., Göpfert, T., Firth, J.D. et al. Influence of hypoxia on hepatic and renal endothelin gene expression. Pflugers Arch. 431, 587–593 (1996).

Download citation

Key words

  • Erythropoietin
  • Oxygen sensing
  • Renal artery stenosis