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Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat

Nature Genetics volume 12, pages 44–51 (1996)Cite this article

Abstract

Hypertension, diabetes and hyperlipidemia are risk factors for life-threatening complications such as end-stage renal disease, coronary artery disease and stroke. Why some patients develop complications is unclear, but only susceptibility genes may be involved. To test this notion, we studied crosses involving the fawn-hooded rat, an animal model of hypertension that develops chronic renal failure. Here, we report the localization of two genes, Rf-1 and Rf-2, responsible for about half of the genetic variation in key indices of renal impairment. In addition, we localize a gene, Bpfh-1, responsible for about 26% of the genetic variation in blood pressure. Rf-1 strongly affects the risk of renal impairment, but has no significant effect on blood pressure. Our results show that susceptibility to a complication of hypertension is under at least partially independent genetic control from susceptibility to hypertension itself.

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References

  1. Roccella, E.J. National high blood pressure education program working group report on hypertension and chronic renal failure. Arch. Int. Med. 51, 1280–1287 (1991).

    Google Scholar 

  2. USRDS 1994 Annual Data Report, IV Incidence and causes of treated ESRD. Am. J. Kid Dis. 24 (suppl2), S48–S56 (1994).

  3. Freedman, B.I., Iskandar, S.S., Appel, R.G. The link between hypertension and nephrosclerosis. Am. J. Kid. Dis. 25, 207–221 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Brazy, P.C., Stead, W.W., Fitzwilliam, J.F. Progression to renal insufficiency: Role of blood pressure. Kidney Int. 35, 670–674 (1989).

    Article  CAS  PubMed  Google Scholar 

  5. Shulman, N.B. et al. Prognostic value of serum creatinine and effect of treatment of hypertension on renal failure. Hypertension. 13, 180–193 (1989).

    Article  Google Scholar 

  6. Perneger, T.V., Klag, M.J., Feldman, H.I. & Whetton, R.K. Projections of hypertension-related renal disease in middle-aged residents of the United States. J. Am. Med. Assoc. 269, 1272–1277 (1993).

    Article  CAS  Google Scholar 

  7. Brancati, F.L., Whetton, R.K., Whittle, J.C & Klag, M.J. Epidemiologic analysis of existing data to investigate hypertensive renal disease: an example from the Maryland End-Stage Renal Disease Registry. Am. J. Kid. Dis. 21, 815–824 (1993).

    Article  Google Scholar 

  8. Jones, C.A. & L Kidney disease and hypertension in blacks: scope of the problem. Am. J. Kid. Dis. 21, S6–S9 (1993).

    Article  Google Scholar 

  9. McClellan, W. Hypertensive end-stage renal disease in blacks: the role of end-stage renal disease surveillance. Am. J. Kid. Dis. 21, S25–S30 (1993).

    Article  Google Scholar 

  10. Freedman, B.I., Spray, B.J., Tuttle, A.B. & Buckalew, V.M. The familial risk of end-stage renal disease in African Americans. Am. J. Kid. Dis. 21, 387–393 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Raymond, S.L. & Dodds, W.J. Characterization of the fawn-hooded rat as a model for hemostatic studies. Thrombos. Diath. Haemostas. 33, 361–369 (1975).

    Article  CAS  Google Scholar 

  12. Prieur, D.L. & Meyers, K.M. Genetics of the fawn-hooded rat strain. J. Hereof. 75, 349–352 (1984).

    Article  CAS  Google Scholar 

  13. Gilboa, N., Rudofsky, U. & Magro, A. Urinary and renal kallikrein in hypertensive fawn-hooded (FH/Wjd) rats. Lab. Invest. 50, 72–78 (1984).

    CAS  PubMed  Google Scholar 

  14. Kuijpers, M.H. & de Jong, J.W. Relationship between blood pressure level, renal histopathological lesions and plasma renin activity in fawn-hooded rats. Br. J. Exp. Pathol. 68, 179–187 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Simons, J.L. et al. Pathogenesis of glomerular injury in the fawn-hooded rat: Early glomerular capillary hypertension predicts glomerular sclerosis. J. Am. Soc. Nephrol. 3, 1775–1782 (1993).

    CAS  PubMed  Google Scholar 

  16. Kreisberg, J.I. & Karnovsky, M.J. Focal glomerular sclerosis in the fawn-hooded rat. Am. J. Pathol. 92, 637–652 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kuijpers, M.H. & Gruys, E. Spontaneous hypertension and hypertensive renal disease in the fawn-hooded rat. Br. J. Exp. Pathol. 65, 181–190 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. The Laboratory Rat: Biology and Disease. (Baker, H.J., Lindsey, J.R., Weisbroth, S.H., eds) Vol. 1,88–91 (Academic Press, San Diego, 1979).

  19. Simons, J.L. et al. Modulation of glomerular hypertension defines susceptibility to progressive glomerular injury. Kidney Int. 46, 396–404 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Westenend, P.J., Nooyen, Y.A., van der Krogt, J.A., van Brummelen, P. & Weening, J.J. The effect of a converting enzyme inhibitor upon renal damage in spontaneously hypertensive Fawn Hooded rats. J. Hypertens. 10, 417–422 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Provoost, A.P., Sterk, J.T., Verseput, G.H., Weening, J.J. Simultaneous reduction of blood pressure and proteinuria by chronic angiotension converting enzyme (ACE) inhibition in hypertensive fawn-hooded (FHH) rats. Kidney Int. 46, 1464 (1994).

    Google Scholar 

  22. Dietrich, W. et al. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell 75, 631–639 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Jacob, H.J. et al. A genetic linkage map of the laboratory rat, Rattus Novegicus. Nature Genet. 9, 63–69 (1995).

    Google Scholar 

  24. Iwai, N. & Inagami, T. Isolation of preferentially expressed genes in the kidneys of hypertensive rats. Hypertension. 17, 161–169 (1991).

    Article  CAS  PubMed  Google Scholar 

  25. Jacob, H.J. et al. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell 67, 213–224 (1991).

    Article  CAS  PubMed  Google Scholar 

  26. Hilbert, P. et al. Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats. Nature. 353, 521–529 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. Cicila, G.T. et al. Linkage of 11 -β hydroxylase mutations with altered steriod biosynthesis and blood pressure in the Dahl rat. Nature Genet. 3, 346–353 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. Dubay, C. et al. Genetic determinates of diastolic and pulse pressure map to different loci in Lyon hypertensive rats. Nature Genet. 3, 354–357 (1993).

    Article  CAS  PubMed  Google Scholar 

  29. Lindpaintner, K. et al. Molecular genetics of the SA-gene: cosegregation with hypertension and mapping to rat chromosome 1. J. Hypertens. 11, 19–23 (1993).

    Article  CAS  PubMed  Google Scholar 

  30. Nabika, T., Nara, Y., Ikeda, K., Endo, J. & Yamori, Y. A new genetic locus cosegregating with blood pressure in F2 progeny obtained from stroke prone spontaneously hypertensive rats and Wistar-Kyoto rats. J. Hypertens. 11, 13–18 (1993).

    Article  CAS  PubMed  Google Scholar 

  31. Nara, Y. et al. Basal high blood pressure cosegregates with the loci on chromosome 1 in the F2 generation from crosses between normotensive Wistar Kyoto rats and stroke-prone spontaneously hypertensive rats. Biochem. Biophys. Res. Commun. 194, 1344–1351 (1993).

    CAS  Google Scholar 

  32. Samani, N.J. et al. A gene differentially expressed in the kidney of the spontaneously hypertensive rat cosegregates with increased blood pressure. J. Clin. Invest. 92, 1099–1103 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Harris, E.L., Dene, H. & Rapp, J.R. SA gene and blood pressure cosegregation using Dahl salt-sensitive rats. Am. J. Hypertens. 6, 330–334 (1993).

    Article  CAS  PubMed  Google Scholar 

  34. Ferguson, R., Grim, C.E. & Opgenorth, T.J. A familial risk of chronic renal failure among blacks on dialysis?. J. Clin. Epidemiol. 41, 1189–1196 (1988).

    Article  CAS  PubMed  Google Scholar 

  35. Berty, R.M., Zeigler, Z.R. & Bruns, F.J. Potentiation of uremic bleeding by hereditary storage pool disease. Am. J. Kid. Dis. 19, 326–330 (1992).

    Article  CAS  PubMed  Google Scholar 

  36. Gawaz, M.R., Bogner, C. & Gurland, H.J. Flow-cytometric analysis of mepacrine-labelled platelets in patients with end-stage renal failure. Hemostasis 23, 284–292 (1993).

    CAS  Google Scholar 

  37. Michalak, E., Walkowiak, B., Paradowski, M. & Ciemiewski, C.S. The decreased circulating platelet mass and its relation to bleeding time in chronic renal failure. Thromb. Haem. 65, 11–14 (1991).

    Article  CAS  Google Scholar 

  38. Soslau, G. et al. Desmopressin-induced improvement in bleeding times in chronic renal failure patients correlates with platelet serotonin uptake and ATP release. J. Med. Sc. 300, 372–379 (1991).

    Article  Google Scholar 

  39. Gordge, M.R., Faint, R.W., Rylance, P.B. & Neild, G.H. Platelet function and the bleeding time in progressive renal failure. Thromb. Haemostasis. 60, 83–87 (1989).

    Google Scholar 

  40. Morel, L., Rudofsky, U.H., Longmate, J A., Schiffenbauer, J., & Wakeland, E.K. Polygenic control of susceptibility to murine systemic lupus erythematosus. Immunity. 1, 219–229 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. Iwai, N., Ohmichi, N., Hanai, K., Nakamura, Y. & Kinoshita, M. Human SA gene locus as a candidate locus for essential hypertension. Hypertension. 23, 375–380 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Provoost, A.P. et al. Spontaneous glomerular sclerosis: insights from the fawn-hooded rat. Kidney Int.. 45, S1–S4 (1994).

    Article  Google Scholar 

  43. Brandis, A., Bianchi, G., Reale, E., Helmchen, U. & Kuhn, K. Age dependent glomerularsclerosis and proteinuria occurring in the rats of Milan Normotensive strain and not in rats of the Milan Hypertensive strain. Lab. Invest. 55, 234–243 (1986).

    CAS  PubMed  Google Scholar 

  44. Hostetter, T.H., Olson, J.L., Rennke, H.G., Venkatachalam, M.A., Brenner, B.M. Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am. J. Phystol. 241, F85–F93 (1981).

    CAS  Google Scholar 

  45. Brenner, B.M., Meyer, T.W. & Hostetter, T.H. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamicalry mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N. Engl. J. Med. 307, 652–659 (1982).

    Article  CAS  PubMed  Google Scholar 

  46. Chung, O., Chung, O., Rohmeiss, R., Sooner, G., Strauch, M. & Gretz, N. Renal involvement in spontaneously hypertensive rats. in Rat Models of Chronic Renal Failure (Gretz, N. & Strauch, M., eds). 357–340 (Karger, Basel, 1993).

    Google Scholar 

  47. Tschopp, T.B. & Zucker, M.B. Hereditary defect in platelet function in rats. Blood 40, 217–226 (1972).

    CAS  PubMed  Google Scholar 

  48. Provoost, A.P. & DeKeijzer, M.H. The fawn-hooded rat: a model for chronic renal failure. In Experimental and Genetic Models of Chronic Renal Failure(eds. Gretz, N. & Strauch, M.) 100–114 (Karger, Basel, 1993).

    Google Scholar 

  49. Fabiny, D.L. & Ertinghausen, G. Automated reaction-rate method determination of serum creatinine with the CentriChem. Clin. Chem. 17, 696–700 (1971).

    CAS  PubMed  Google Scholar 

  50. Talke, H. & Schubert, G.E., Hamstoffbestimmung in Blut and Serum im optischen Test nach Warburg. Klin. Wochenschr. 43, 174–175 (1965).

    Article  CAS  PubMed  Google Scholar 

  51. Serikawa, T. et al. Rat gene map using PCR-microsatellites. Genetics 121, 701–721 (1992).

    Google Scholar 

  52. Laird, R.W. et al. Simplified mammalian DNA isolation procedure. Nucl. Acids Res. 19, 4293 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Szpirer, J., Levan, G., Thorn, M. & Szpirer, C. Gene mapping in the rat by mouse-rat somatic cell hybridization: synteny of the albumin and alpha-fetoprotein genes and assignment to chromosome 14. Cyfogenef. Cell Genet. 38, 142–149 (1984).

    Article  CAS  Google Scholar 

  54. Lander, E.S. et al. MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. Genomics. 1, 174–181 (1987).

    Article  CAS  PubMed  Google Scholar 

  55. Lincoln, S.E. & Lander, E.S. Systematic detection of errors in genetic linkage data. Genomics. 14, 604–610 (1992).

    Article  CAS  PubMed  Google Scholar 

  56. Lander, E.S. & Botstein, D. Mapping mendelian factors underlying quantitative traits using RFLP linkage maps. Genetics 121, 185–199 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

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Author notes

  1. Donna M. Brown: Research Genetics, Huntsville, Alabama 35801, USA.

  2. Howard J. Jacob: Correspondence should be addressed to H.J.J.

Authors and Affiliations

  1. Cardiovascular Research Center, Massachusetts General Hospital/ Harvard Medical School, Charlestown, Massachusetts, 02129, USA

    Donna M. Brown & Howard J. Jacob

  2. Department of Pediatric Surgery, Erasmus University, Rotterdam, The Netherlands

    Abraham P. Provoost

  3. Whitehead Institute for Biomedical Research/MIT Center for Genome Research, Cambridge, Masssachusetts, 02142, USA

    Mark J. Daly, Eric S. Lander & Howard J. Jacob

  4. MIT Dept. of Biology, Cambridge, Massachusetts, 02139, USA

    Eric S. Lander

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  4. Eric S. Lander
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  5. Howard J. Jacob
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Brown, D., Provoost, A., Daly, M. et al. Renal disease susceptibility and hypertension are under independent genetic control in the fawn-hooded rat. Nat Genet 12, 44–51 (1996). https://doi.org/10.1038/ng0196-44

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  • DOI: https://doi.org/10.1038/ng0196-44

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