Gene Mapping in Experimental Hypertension

  • T. W. Kurtz
  • L. Simonet
  • V. Křen
  • M. Pravenec

Summary

The spontaneously hypertensive rat (SHR) is the most widely studied animal model of hypertension and it has been proposed that the identification of genes contributing to increased blood pressure in the SHR might shed light on the pathogenesis of essential hypertension in humans. In F2, backcross, and recombinant inbred populations derived from the SHR and inbred normotensive strains, one can search for chromosome regions that contain genes regulating blood pressure by studying the relationship between blood pressure and the pattern of inheritance of:
  1. 1.

    polymorphic markers for specific genes believed to be related to the pathogenesis of hypertension (so-called “candidate” gene approach), and/or

     
  2. 2.

    a mapped set of polymorphic markers dispersed throughout the rodent genome (so-called “reverse” genetics approach).

     

Using the “candidate” gene approach, we have found evidence suggesting that, in the rat, sequence variation within or near the renin gene, the kallikrein gene family, and the RT1 gene complex may have the capacity to affect blood pressure. With respect to the “reverse” genetics approach, we are attempting to develop a rough genetic map that can be used to study the pathogenesis of hypertension in SHR. To date, we have identified over 70 polymorphic markers that distinguish between the SHR and a normotensive Brown-Norway (BN) strain. Analysis of a large set of recombinant inbred strains derived from the SHR and BN progenitors indicates that most of these markers are not tightly linked. These observations suggest that, in the SHR, it should be feasible to employ both the “candidate” gene and “reverse” genetics approaches to search for chromosome regions that contain genes regulating blood pressure.

Keywords

Recombinant Inbred Recombinant Inbred Strain Affect Blood Pressure Experimental Hypertension Renin Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Barnes FM (1989) Troubles encountered in gene linkage land. Science 243: 313–314PubMedCrossRefGoogle Scholar
  2. Bunag RD (1983) Facts and fallacies about measuring blood pressure in rats. Clin Exp Hypertens [A] 5 (10): 1659–1681CrossRefGoogle Scholar
  3. Cawthon RM, Weiss R, Xu G, Viskochil D, Dunn D, Gesteland R, O’Connell P, White R (1990) A major segment of neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62: 193–201PubMedCrossRefGoogle Scholar
  4. Chakravarti A, Majumder PP (1989) Strategies for mapping traits using a genome map. Cold Spring Harbor Symp Genome Mapping 32Google Scholar
  5. Chotai J (1984) On the lod score method in linkage analysis. Ann Hum Genet 48: 359–378PubMedCrossRefGoogle Scholar
  6. Cramer DV (1983) Genetic monitoring techniques in rats. ILAR News 16: 15–20Google Scholar
  7. Ely DL, Turner ME (1990) Hypertension in the spontaneously hypertensive rat is linked to the Y chromosome. Hypertension 16: 277–281PubMedGoogle Scholar
  8. Ferrari AU, Daffonchio A, Albergati F, Berotoli P, Mancia G (1990) Intra-arterial pressure alterations during tail-cuff blood pressure measurements in normotensive and hypertensive rats. J Hypertens 8: 909–912PubMedCrossRefGoogle Scholar
  9. Festing MFW (1982) Genetic contamination of laboratory animal colonies: an increasingly serious problem. ILAR News 15: 6–8Google Scholar
  10. Frohlich ED, Trippodo NC (1981) Similarities of genetic (spontaneous) hypertension: man and rat. Circ Res 48: 309–319PubMedGoogle Scholar
  11. Gerbase-DeLima M, Delima JJG, Persoli LB, Bernardes Silva H, Marcondes M, Bellotti G (1989) Essential hypertension and histocompatibility antigens. Hypertension 14: 604–609PubMedGoogle Scholar
  12. Gray SD (1984) Pressure profiles in neonatal spontaneously hypertensive rats. Biol Neonate 45: 25–32PubMedCrossRefGoogle Scholar
  13. Guidi E, Hollenberg NK (1987) Differential pressor and renal vascular reactivity to angiotensin II in spontaneously hypertensive and Wistar-Kyoto rats. Hypertension 9: 591–597PubMedGoogle Scholar
  14. Jeffreys AJ, Wilson V, Thein SL (1985) Hypervariable minisatellite regions in human DNA. Nature 314: 67–73PubMedCrossRefGoogle Scholar
  15. Julier C, De Gouyon B, Georges M, Gunet J-L, Nakamura Y, Avner P, Lathrop GM (1990) Minisatellite linkage maps in the mouse by cross-hybridization with human probes containing tandem repeats. Proc Natl Acad Sci USA 87: 4585–4589PubMedCrossRefGoogle Scholar
  16. Kurtz TW, Morris RC (1987) Biological variability in Wistar-Kyoto rats: implications for research with the spontaneously hypertensive rat. Hypertension 10: 127–131PubMedGoogle Scholar
  17. Kurtz TW, Montano M, Chan L, Kabra P (1989) Molecular evidence of genetic heterogeneity in Wistar-Kyoto rats: implications for research with the spontaneously hypertensive rat. Hypertension 13: 188–192PubMedGoogle Scholar
  18. Kurtz TW, Simonet L, Kabra PM, Wolfe S, Chan L, Hjelle BL (1990a) Cosegregation of the renin allele of the spontaneously hypertensive rat with an increase in blood pressure. J Clin Invest 85: 1328–1332PubMedCrossRefGoogle Scholar
  19. Kurtz TW, Casto R, Simonet L, Printz M (1990b) Biometrical genetic analysis of blood pressure in the spontaneously hypertensive rat. Hypertension 16: 718–724PubMedGoogle Scholar
  20. Lander Es, Botstein D (1989) Mapping Mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121: 185–199Google Scholar
  21. Lange K, Boehnke M (1982) How many polymorphic genes will it take to span the human genome? Am J Hum Genet 34: 842–845PubMedGoogle Scholar
  22. Lindpainter K, Takahashi S, Ganten D (1990) Structural alterations of the renin gene in stroke-prone spontaneously hypertensive rats: examination of genotype-phenotype correlations. J Hypertens 8: 763–774CrossRefGoogle Scholar
  23. Matsumoto K, Gasser DL (1983) Polymorphism of glutathione 5-transferase in laboratory rats. Biochem Genet 21: 1209–1251PubMedCrossRefGoogle Scholar
  24. Mori M, Ishizaki I, Yamada T, Chen H, Sugiyama T, Serikawa T, Yamada J (1989) Restriction fragment length polymorphism of the angiotensinogen gene in inbred rat strains and mapping of the gene on chromosome 19q. Cytogenet Cell Genet 50: 42–45PubMedCrossRefGoogle Scholar
  25. Mullins JJ, Peters J, Ganten D (1990) Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature 344: 541–544PubMedCrossRefGoogle Scholar
  26. Nakamura Y, Leppert M, O’Connell P, Wolff R, Holm T, Culver M, Martin C, Fujimoto E, Hoff M, Kumlin E, White R (1987) Variable number of tandem repeat ( VNTR) markers for human gene mapping. Science 235: 1616–1622Google Scholar
  27. Ohkubo J, Kawakami H, Kakehi Y, Takumi T, Arai H, Yokota Y, Iwai M, Tanabe Y, Masu M, Hata J, Iwao H, Okamoto H, Yokoyama M, Nomura T, Katsuki M, Nakanishi S (1990) Generation of transgenic mice with elevated blood pressure by introduction of the rat renin gene and angiotensinogen genes. Proc Natl Acad Sci USA 87: 5133–5157CrossRefGoogle Scholar
  28. Okamoto K, Aoki K (1963) Development of a strain of spontaneously hypertensive rats. Jpn Circ J 27: 282–293PubMedCrossRefGoogle Scholar
  29. Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T (1989) Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci USA 86: 2766–2770PubMedCrossRefGoogle Scholar
  30. Paterson AH, DeVerna JW, Lanini B, Tanksley SD (1990) Fine mapping of quantitative trait loci using selected overlapping recombinant chromosomes, in an interspecies cross of tomato. Genetics 124: 735–742PubMedGoogle Scholar
  31. Plomin R (1990) The role of inheritance in behavior. Science 248: 183–188PubMedCrossRefGoogle Scholar
  32. Pravenec M, Klir P, Kren V, Zicha J, Kunes J (1989) An analysis of spontaneous hypertension in spontaneously hypertensive rats by means of new recombinant inbred strains. J Hypertens 7: 217–222PubMedCrossRefGoogle Scholar
  33. Pravenec M, Simonet L, Kren V, Kunes J, Levan G, Szpirer J, Szpirer C, Kurtz T (1991a) The rat renin gene: assignment to chromosome 13 and linkage to the regulation of blood pressure. Genomics 9: 466–472PubMedCrossRefGoogle Scholar
  34. Pravenec M, Kren V, Kunes J, Scicli AG, Carretero OA, Simonet L, Kurtz TW (1991b) Cosegregation of blood pressure with a kallikrein gene family polymorphism. Hypertension 17: 242–246PubMedGoogle Scholar
  35. Rapp JP (1983a) Genetics of experimental and human hypertension. In: Genest J, Kuchel O, Hamet P, Cantin M (eds) Hypertension, pathophysiology and treatment. McGraw-Hill, New York, pp 582–598Google Scholar
  36. Rapp JP (1983b) A paradigm for identification of primary genetic causes of hypertension in rats. Hypertension 5 [Suppl I]: I-198-I-203Google Scholar
  37. Rapp JP (1987) Use an misuse of control strains for genetically hypertensive rats. Hypertension 10: 7–10PubMedGoogle Scholar
  38. Rapp JP, Wang S-M, Dene H (1989) A genetic polymorphism in the renin gene of Dahl rats cosegregates with blood pressure. Science 243: 542–544PubMedCrossRefGoogle Scholar
  39. Samani NJ, Brammar WJ, Swales JD (1989) A major structural abnormality in the renin gene of the spontaneously hypertensive rat. J Hypertens 7: 249–254PubMedGoogle Scholar
  40. Schafer R, Sher A, Epplen JT (1986) The organization of the evolutionarily conserved GATA/GACA repeats in the mouse genome. Chromosoma 93: 502–510PubMedCrossRefGoogle Scholar
  41. Schlager G (1974) Selection for blood pressure levels in mice. Genetics 76: 537–549PubMedGoogle Scholar
  42. Schlager G (1981) The genetically hypertensive mouse. In: Worcel M (ed) Trends in arterial hypertension. North-Holland, New York, pp 321–331Google Scholar
  43. Schlager G (1984) Genetic hypertension in different strains of mice. In: De Jong W (ed) Handbook of hypertension: experimental and genetic models of hypertension. North-Holland, New York, pp 192–199Google Scholar
  44. Tanase H (1979) Genetic control of blood pressure in spontaneously hypertensive rats. Exp Anim 28: 519–530Google Scholar
  45. Tanase H, Suzuki Y, Ooshima A, Yamori Y, Okamoto K (1970) Genetic analysis of blood pressure in spontaneously hypertensive rats. Jpn Circ J 34: 1197–1212PubMedCrossRefGoogle Scholar
  46. Weber MA (1988) Whole-day blood pressure. Hypertension 11: 288–298PubMedGoogle Scholar
  47. Williams GH, Braley LM, Menachery A (1982) Decreased adrenal responsiveness to angiotensin II: A defect present in spontaneously hypertensive rats. J Clin Invest 69: 31–37Google Scholar
  48. Woodley-Miller C, Chao J, Chao L (1989) Restriction fragment length polymorphisms mapped in spontaneously hypertensive rats using kallikrein probes. J Hypertens 7: 865–871PubMedCrossRefGoogle Scholar
  49. Zischler H, Nanda I, Schafer M, Schmid M, Epplen JT (1989) Digoxigenated oligonucleotide probes specific for simple repeats in DNA fingerprinting and hybridization in situ. Hum Genet 82: 227–233PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1991

Authors and Affiliations

  • T. W. Kurtz
  • L. Simonet
  • V. Křen
  • M. Pravenec

There are no affiliations available

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