Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Sep 15;102(6):1102–1111. doi: 10.1172/JCI3868

The alpha1 Na,K-ATPase gene is a susceptibility hypertension gene in the Dahl salt-sensitiveHSD rat.

V L Herrera 1, H X Xie 1, L V Lopez 1, N J Schork 1, N Ruiz-Opazo 1
PMCID: PMC509093  PMID: 9739044

Abstract

Despite the prevalence of essential hypertension, its underlying genetic basis has not been elucidated due to the complexities of its determinants. To identify a hypertension susceptibility gene, we used an approach that integrates molecular, transgenic, and genetic analysis using Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats ascertained for genotype and phenotype. To determine the role of the Dahl S Q276L alpha1 Na,K-ATPase gene variant, we developed transgenic Dahl S rats bearing the Dahl R wild-type (wt) alpha1 Na, K-ATPase cDNA directed by the cognate wt promoter region, Tg[wtalpha1]. Transgenic Dahl S rats exhibited less salt-sensitive hypertension, less hypertensive renal disease, and longer life span when compared with non-transgenic Dahl S controls. Total chromosome 2 linkage analysis of F2(SxR) male rats detects cosegregation of the alpha1 Na,K-ATPase locus with salt-sensitive hypertension. These data support the alpha1 Na,K-ATPase gene as a susceptibility gene for salt-sensitive hypertension in the Dahl S rat model, and provide the basis for the study of the alpha1 Na,K-ATPase locus in human hypertension.

Full Text

The Full Text of this article is available as a PDF (2.7 MB).

Selected References

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

  1. Canessa M., Romero J. R., Ruiz-Opazo N., Herrera V. L. The alpha 1 Na(+)-K+ pump of the Dahl salt-sensitive rat exhibits altered Na+ modulation of K+ transport in red blood cells. J Membr Biol. 1993 Jun;134(2):107–122. doi: 10.1007/BF00232747. [DOI] [PubMed] [Google Scholar]
  2. Clark J. S., Jeffs B., Davidson A. O., Lee W. K., Anderson N. H., Bihoreau M. T., Brosnan M. J., Devlin A. M., Kelman A. W., Lindpaintner K. Quantitative trait loci in genetically hypertensive rats. Possible sex specificity. Hypertension. 1996 Nov;28(5):898–906. doi: 10.1161/01.hyp.28.5.898. [DOI] [PubMed] [Google Scholar]
  3. DAHL L. K., HEINE M., TASSINARI L. Role of genetic factors in susceptibility to experimental hypertension due to chronic excess salt ingestion. Nature. 1962 May 5;194:480–482. doi: 10.1038/194480b0. [DOI] [PubMed] [Google Scholar]
  4. Dahl L. K., Heine M., Thompson K. Genetic influence of the kidneys on blood pressure. Evidence from chronic renal homografts in rats with opposite predispositions to hypertension. Circ Res. 1974 Jan;34(1):94–101. doi: 10.1161/01.res.40.4.94. [DOI] [PubMed] [Google Scholar]
  5. Dallner G. Isolation of rough and smooth microsomes--general. Methods Enzymol. 1974;31:191–201. [PubMed] [Google Scholar]
  6. Deng A. Y., Dene H., Rapp J. P. Mapping of a quantitative trait locus for blood pressure on rat chromosome 2. J Clin Invest. 1994 Jul;94(1):431–436. doi: 10.1172/JCI117341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dubay C., Vincent M., Samani N. J., Hilbert P., Kaiser M. A., Beressi J. P., Kotelevtsev Y., Beckmann J. S., Soubrier F., Sassard J. Genetic determinants of diastolic and pulse pressure map to different loci in Lyon hypertensive rats. Nat Genet. 1993 Apr;3(4):354–357. doi: 10.1038/ng0493-354. [DOI] [PubMed] [Google Scholar]
  8. Goldman D. High anxiety. Science. 1996 Nov 29;274(5292):1483–1483. doi: 10.1126/science.274.5292.1483. [DOI] [PubMed] [Google Scholar]
  9. Herrera V. L., Cova T., Sassoon D., Ruiz-Opazo N. Developmental cell-specific regulation of Na(+)-K(+)-ATPase alpha 1-, alpha 2-, and alpha 3-isoform gene expression. Am J Physiol. 1994 May;266(5 Pt 1):C1301–C1312. doi: 10.1152/ajpcell.1994.266.5.C1301. [DOI] [PubMed] [Google Scholar]
  10. Herrera V. L., Ruiz-Opazo N. Alteration of alpha 1 Na+,K(+)-ATPase 86Rb+ influx by a single amino acid substitution. Science. 1990 Aug 31;249(4972):1023–1026. doi: 10.1126/science.1975705. [DOI] [PubMed] [Google Scholar]
  11. Herrera V. L., Ruiz-Opazo N. Beyond genetic markers: hypertension genes. J Hypertens. 1994 Aug;12(8):847–856. [PubMed] [Google Scholar]
  12. Jacob H. J., Brown D. M., Bunker R. K., Daly M. J., Dzau V. J., Goodman A., Koike G., Kren V., Kurtz T., Lernmark A. A genetic linkage map of the laboratory rat, Rattus norvegicus. Nat Genet. 1995 Jan;9(1):63–69. doi: 10.1038/ng0195-63. [DOI] [PubMed] [Google Scholar]
  13. Lander E. S., Schork N. J. Genetic dissection of complex traits. Science. 1994 Sep 30;265(5181):2037–2048. doi: 10.1126/science.8091226. [DOI] [PubMed] [Google Scholar]
  14. Lander E., Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet. 1995 Nov;11(3):241–247. doi: 10.1038/ng1195-241. [DOI] [PubMed] [Google Scholar]
  15. Lesch K. P., Bengel D., Heils A., Sabol S. Z., Greenberg B. D., Petri S., Benjamin J., Müller C. R., Hamer D. H., Murphy D. L. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science. 1996 Nov 29;274(5292):1527–1531. doi: 10.1126/science.274.5292.1527. [DOI] [PubMed] [Google Scholar]
  16. Lewis J. L., Russell R. J., Warnock D. G. Analysis of the genetic contamination of salt-sensitive Dahl/Rapp rats. Hypertension. 1994 Sep;24(3):255–259. doi: 10.1161/01.hyp.24.3.255. [DOI] [PubMed] [Google Scholar]
  17. Orosz D. E., Hopfer U. Pathophysiological consequences of changes in the coupling ratio of Na,K-ATPase for renal sodium reabsorption and its implications for hypertension. Hypertension. 1996 Feb;27(2):219–227. doi: 10.1161/01.hyp.27.2.219. [DOI] [PubMed] [Google Scholar]
  18. Raij L., Azar S., Keane W. Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int. 1984 Aug;26(2):137–143. doi: 10.1038/ki.1984.147. [DOI] [PubMed] [Google Scholar]
  19. Rapp J. P., Dene H. Development and characteristics of inbred strains of Dahl salt-sensitive and salt-resistant rats. Hypertension. 1985 May-Jun;7(3 Pt 1):340–349. [PubMed] [Google Scholar]
  20. Ruiz-Opazo N., Barany F., Hirayama K., Herrera V. L. Confirmation of mutant alpha 1 Na,K-ATPase gene and transcript in Dahl salt-sensitive/JR rats. Hypertension. 1994 Sep;24(3):260–270. doi: 10.1161/01.hyp.24.3.260. [DOI] [PubMed] [Google Scholar]
  21. Ruiz-Opazo N., Cloix J. F., Melis M. G., Xiang X. H., Herrera V. L. Characterization of a sodium-response transcriptional mechanism. Hypertension. 1997 Aug;30(2 Pt 1):191–198. doi: 10.1161/01.hyp.30.2.191. [DOI] [PubMed] [Google Scholar]
  22. Ruiz-Opazo N., Xiang X. H., Herrera V. L. Pressure-overload deinduction of human alpha 2 Na,K-ATPase gene expression in transgenic rats. Hypertension. 1997 Feb;29(2):606–612. doi: 10.1161/01.hyp.29.2.606. [DOI] [PubMed] [Google Scholar]
  23. Samani N. J., Gauguier D., Vincent M., Kaiser M. A., Bihoreau M. T., Lodwick D., Wallis R., Parent V., Kimber P., Rattray F. Analysis of quantitative trait loci for blood pressure on rat chromosomes 2 and 13. Age-related differences in effect. Hypertension. 1996 Dec;28(6):1118–1122. doi: 10.1161/01.hyp.28.6.1118. [DOI] [PubMed] [Google Scholar]
  24. Shull G. E., Greeb J., Lingrel J. B. Molecular cloning of three distinct forms of the Na+,K+-ATPase alpha-subunit from rat brain. Biochemistry. 1986 Dec 16;25(25):8125–8132. doi: 10.1021/bi00373a001. [DOI] [PubMed] [Google Scholar]
  25. Simonet L., St Lezin E., Kurtz T. W. Sequence analysis of the alpha 1 Na+,K(+)-ATPase gene in the Dahl salt-sensitive rat. Hypertension. 1991 Nov;18(5):689–693. doi: 10.1161/01.hyp.18.5.689. [DOI] [PubMed] [Google Scholar]
  26. St Lezin E. M., Pravenec M., Wong A., Wang J. M., Merriouns T., Newton S., Stec D. E., Roman R. J., Lau D., Morris R. C., Jr Genetic contamination of Dahl SS/Jr rats. Impact on studies of salt-sensitive hypertension. Hypertension. 1994 Jun;23(6 Pt 1):786–790. doi: 10.1161/01.hyp.23.6.786. [DOI] [PubMed] [Google Scholar]
  27. de Wardener H. E. The primary role of the kidney and salt intake in the aetiology of essential hypertension: Part II. Clin Sci (Lond) 1990 Oct;79(4):289–297. doi: 10.1042/cs0790289. [DOI] [PubMed] [Google Scholar]

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

RESOURCES