Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Mar;89(3):753–760. doi: 10.1172/JCI115652

Age-dependent expression of the erythropoietin gene in rat liver and kidneys.

K U Eckardt 1, P J Ratcliffe 1, C C Tan 1, C Bauer 1, A Kurtz 1
PMCID: PMC442918  PMID: 1541670

Abstract

Using RNAse protection, we have made quantitative measurements of erythropoietin (EPO) mRNA in liver and kidneys of developing rats (days 1-54), to determine the relative contribution of both organs to the total EPO mRNA, to monitor changes which occur with development, and to compare the hypoxia-induced accumulation of EPO mRNA with the changes in serum EPO concentrations. To determine whether developmental and organ-specific responsiveness is related to the type of hypoxic stimulus, normobaric hypoxia was compared with exposure to carbon monoxide (functional anemia). Under both stimuli EPO mRNA concentration in liver was maximal on day 7 and declined during development. In contrast, EPO mRNA concentration in kidney increased during development from day 1 when it was 30-65% the hepatic concentration to day 54 when it was 12-fold higher than in liver. When organ weight was considered the liver was found to contain the majority of EPO mRNA in the first three to four weeks of life, and although, in stimulated animals, the hepatic proportion declined from 85-91% on day 1, it remained approximately 33% at day 54 and was similar for the two types of stimuli. When normalized for body weight the sum of renal and hepatic EPO mRNA in animals of a particular age was related linearly to serum hormone concentrations. However, the slope of this regression increased progressively with development, suggesting age-dependent alterations in translational efficiency or EPO metabolism.

Full text

PDF
753

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abbrecht P. H., Littell J. K. Plasma erythropoietin in men and mice during acclimatization to different altitudes. J Appl Physiol. 1972 Jan;32(1):54–58. doi: 10.1152/jappl.1972.32.1.54. [DOI] [PubMed] [Google Scholar]
  2. Beru N., McDonald J., Lacombe C., Goldwasser E. Expression of the erythropoietin gene. Mol Cell Biol. 1986 Jul;6(7):2571–2575. doi: 10.1128/mcb.6.7.2571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bondurant M. C., Koury M. J. Anemia induces accumulation of erythropoietin mRNA in the kidney and liver. Mol Cell Biol. 1986 Jul;6(7):2731–2733. doi: 10.1128/mcb.6.7.2731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Carmena A. O., Howard D., Stohlman F., Jr Regulation of erythropoiesis. XXII. Erythropoietin production in the newborn animal. Blood. 1968 Sep;32(3):376–382. [PubMed] [Google Scholar]
  5. Caro J., Erslev A. J., Silver R., Miller O., Birgegard G. Erythropoietin production in response to anemia or hypoxia in the newborn rat. Blood. 1982 Oct;60(4):984–988. [PubMed] [Google Scholar]
  6. Clemons G. K., Fitzsimmons S. L., DeManincor D. Immunoreactive erythropoietin concentrations in fetal and neonatal rats and the effects of hypoxia. Blood. 1986 Oct;68(4):892–899. [PubMed] [Google Scholar]
  7. Cotes P. M., Pippard M. J., Reid C. D., Winearls C. G., Oliver D. O., Royston J. P. Characterization of the anaemia of chronic renal failure and the mode of its correction by a preparation of human erythropoietin (r-HuEPO). An investigation of the pharmacokinetics of intravenous erythropoietin and its effects on erythrokinetics. Q J Med. 1989 Feb;70(262):113–137. [PubMed] [Google Scholar]
  8. Eckardt K. U., Boutellier U., Kurtz A., Schopen M., Koller E. A., Bauer C. Rate of erythropoietin formation in humans in response to acute hypobaric hypoxia. J Appl Physiol (1985) 1989 Apr;66(4):1785–1788. doi: 10.1152/jappl.1989.66.4.1785. [DOI] [PubMed] [Google Scholar]
  9. Eckardt K. U., Dittmer J., Neumann R., Bauer C., Kurtz A. Decline of erythropoietin formation at continuous hypoxia is not due to feedback inhibition. Am J Physiol. 1990 May;258(5 Pt 2):F1432–F1437. doi: 10.1152/ajprenal.1990.258.5.F1432. [DOI] [PubMed] [Google Scholar]
  10. Eckardt K. U., Kurtz A., Hirth P., Scigalla P., Wieczorek L., Bauer C. Evaluation of the stability of human erythropoietin in samples for radioimmunoassay. Klin Wochenschr. 1988 Mar 15;66(6):241–245. doi: 10.1007/BF01748163. [DOI] [PubMed] [Google Scholar]
  11. Erslev A. J., Caro J., Kansu E., Silver R. Renal and extrarenal erythropoietin production in anaemic rats. Br J Haematol. 1980 May;45(1):65–72. doi: 10.1111/j.1365-2141.1980.tb03811.x. [DOI] [PubMed] [Google Scholar]
  12. Fried W., Barone-Varelas J., Barone T. The influence of age and sex on erythropoietin titers in the plasma and tissue homogenates of hypoxic rats. Exp Hematol. 1982 May;10(5):472–477. [PubMed] [Google Scholar]
  13. Fried W. The liver as a source of extrarenal erythropoietin production. Blood. 1972 Nov;40(5):671–677. [PubMed] [Google Scholar]
  14. Gruber D. F., Zucali J. R., Wleklinski J., LaRussa V., Mirand E. A. Temporal transition in the site of rat erythropoietin production. Exp Hematol. 1977 Sep;5(5):399–407. [PubMed] [Google Scholar]
  15. JACOBSON L. O., GOLDWASSER E., FRIED W., PLZAK L. Role of the kidney in erythropoiesis. Nature. 1957 Mar 23;179(4560):633–634. doi: 10.1038/179633a0. [DOI] [PubMed] [Google Scholar]
  16. Koury M. J., Bondurant M. C., Graber S. E., Sawyer S. T. Erythropoietin messenger RNA levels in developing mice and transfer of 125I-erythropoietin by the placenta. J Clin Invest. 1988 Jul;82(1):154–159. doi: 10.1172/JCI113564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Koury S. T., Bondurant M. C., Koury M. J., Semenza G. L. Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood. 1991 Jun 1;77(11):2497–2503. [PubMed] [Google Scholar]
  18. Koury S. T., Koury M. J., Bondurant M. C., Caro J., Graber S. E. Quantitation of erythropoietin-producing cells in kidneys of mice by in situ hybridization: correlation with hematocrit, renal erythropoietin mRNA, and serum erythropoietin concentration. Blood. 1989 Aug 1;74(2):645–651. [PubMed] [Google Scholar]
  19. Peschle C., Marone G., Genovese A., Cillo C., Magli C., Condorelli M. Erythropoietin production by the liver in fetal-neonatal life. Life Sci. 1975 Oct 15;17(8):1325–1330. doi: 10.1016/0024-3205(75)90146-0. [DOI] [PubMed] [Google Scholar]
  20. Potter C. G., Tan C. C., Ratcliffe P. J. Quantification of 32P-labeled samples in gel fragments using the flat-bed liquid scintillation counter. Anal Biochem. 1991 Aug 15;197(1):121–124. doi: 10.1016/0003-2697(91)90366-2. [DOI] [PubMed] [Google Scholar]
  21. Ratcliffe P. J., Jones R. W., Phillips R. E., Nicholls L. G., Bell J. I. Oxygen-dependent modulation of erythropoietin mRNA levels in isolated rat kidneys studied by RNase protection. J Exp Med. 1990 Aug 1;172(2):657–660. doi: 10.1084/jem.172.2.657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ruth V., Widness J. A., Clemons G., Raivio K. O. Postnatal changes in serum immunoreactive erythropoietin in relation to hypoxia before and after birth. J Pediatr. 1990 Jun;116(6):950–954. doi: 10.1016/s0022-3476(05)80659-6. [DOI] [PubMed] [Google Scholar]
  23. Schooley J. C., Mahlmann L. J. Erythropoietin production in the anephric rat. I. Relationship between nephrectomy, time of hypoxic exposure, and erythropoietin production. Blood. 1972 Jan;39(1):31–38. [PubMed] [Google Scholar]
  24. Schuster S. J., Badiavas E. V., Costa-Giomi P., Weinmann R., Erslev A. J., Caro J. Stimulation of erythropoietin gene transcription during hypoxia and cobalt exposure. Blood. 1989 Jan;73(1):13–16. [PubMed] [Google Scholar]
  25. Spivak J. L., Hogans B. B. The in vivo metabolism of recombinant human erythropoietin in the rat. Blood. 1989 Jan;73(1):90–99. [PubMed] [Google Scholar]
  26. Tan C. C., Eckardt K. U., Ratcliffe P. J. Organ distribution of erythropoietin messenger RNA in normal and uremic rats. Kidney Int. 1991 Jul;40(1):69–76. doi: 10.1038/ki.1991.181. [DOI] [PubMed] [Google Scholar]
  27. Wang F., Fried W. Renal and extrarenal erythropoietin production in male and female rats of various ages. J Lab Clin Med. 1972 Feb;79(2):181–186. [PubMed] [Google Scholar]
  28. Zanjani E. D., Ascensao J. L., McGlave P. B., Banisadre M., Ash R. C. Studies on the liver to kidney switch of erythropoietin production. J Clin Invest. 1981 Apr;67(4):1183–1188. doi: 10.1172/JCI110133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Zanjani E. D., Peterson E. N., Gordon A. S., Wasserman L. R. Erythropoietin production in the fetus: role of the kidney and maternal anemia. J Lab Clin Med. 1974 Feb;83(2):281–287. [PubMed] [Google Scholar]
  30. Zanjani E. D., Poster J., Burlington H., Mann L. I., Wasserman L. R. Liver as the primary site of erythropoietin formation in the fetus. J Lab Clin Med. 1977 Mar;89(3):640–644. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES