Although there has been significant progress in the investigation of the genetic basis of hypertension, much work remains to be done against the cumulative backdrop of persistent clinical mandates. In essence, essential hypertension remains a highly prevalent disease and remains a major risk factor for the top causes of mortality in the USA: coronary artery disease, heart failure, arrhythmias. stroke and renal disease. It has become clear that (1) gene interaction must be factored into the genetic analysis of complex genetic diseases, (e.g., essential hypertension); and that (2) gene interaction analysis in well-controlled animal model experiments coupled to prioritized subsequent testing in genetically isolated human populations provides a robust experimental strategy. These realizations along with insights, observations, as well as experimental approach validation obtained in the previous research proposal, provide us with the clinical and scientific mandates to investigate the following hypothesis: The unidirectional gene interaction of a1 Na,K-ATPase (a1NK) and Na,K,2C1-cotransporter (NKC) genes increasing susceptibility to hypertension identified in Dahl S rats by an intercross linkage analysis reflects an in vivo molecular interdependence of these transporters and as such it should be amenable to in vivo testing via strategic transgenic experiments. Accordingly, the following specific aims are prioritized for this continuing research proposal:
Aim I : Determine the in vivo biological significance of the genetic correlation of the renal-specific Na,K,2Cl-cotransporter gene with hypertension in Dahl S rats.
Aim II : Determine the in vivo biological significance of the statistical interactive correlation of a1NK and NKC genes on salt-sensitive hypertension by developing dual transgenic (bigenic) Tg[Ra 1NK x nkc-F)] and Tg[Ra 1NK x nkc-A)] Dahl S rats. The successful completion of this research program will define a) the alNa,K-ATPase and the bumetanide-sensitive Na,K,2Cl-cotransporter as bona fide hypertension susceptibility genes in Dahl S rats; and b) will pave the way for the direct assessment of the role of these genes in hypertension susceptibility in different human populations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL058136-04A2
Application #
6468775
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Lin, Michael
Project Start
1998-01-15
Project End
2006-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
4
Fiscal Year
2002
Total Cost
$326,000
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Herrera, Victoria L; Ponce, Lorenz R; Ruiz-Opazo, Nelson (2013) Multiple susceptibility loci for radiation-induced mammary tumorigenesis in F2[Dahl S x R]-intercross rats. PLoS One 8:e72143
Herrera, Victoria L M; Tsikoudakis, Aristides; Ponce, Lorenz R B et al. (2006) Sex-specific QTLs and interacting loci underlie salt-sensitive hypertension and target organ complications in Dahl S/jrHS hypertensive rats. Physiol Genomics 26:172-9
Herrera, Victoria L M; Ruiz-Opazo, Nelson (2005) Genetic studies in rat models: insights into cardiovascular disease. Curr Opin Lipidol 16:179-91
Kaneko, Yuji; Cloix, Jean-Francois; Herrera, Victoria Lm et al. (2005) Corroboration of Dahl S Q276L alpha1Na,K-ATPase protein sequence: impact on affinities for ligands and on E1 conformation. J Hypertens 23:745-52
Herrera, Victoria L M; Traverse, Sarah; Lopez, Lyle V et al. (2003) X-linked locus associated with hypertensive renal disease susceptibility in Dahl rats. J Hypertens 21:67-71
Herrera, V L; Lopez, L V; Ruiz-Opazo, N (2001) Alpha1 Na,K-ATPase and Na,K,2Cl-cotransporte/D3mit3 loci interact to increase susceptibility to salt-sensitive hypertension in Dahl S(HSD) rats. Mol Med 7:125-34
Glorioso, N; Filigheddu, F; Troffa, C et al. (2001) Interaction of alpha(1)-Na,K-ATPase and Na,K,2Cl-cotransporter genes in human essential hypertension. Hypertension 38:204-9
Song, Y; Herrera, V L; Filigheddu, F et al. (2001) Non-association of the thiazide-sensitive Na,Cl-cotransporter gene with polygenic hypertension in both rats and humans. J Hypertens 19:1547-51
Herrera, V L; Xie, H X; Lopez, L V et al. (1998) The alpha1 Na,K-ATPase gene is a susceptibility hypertension gene in the Dahl salt-sensitiveHSD rat. J Clin Invest 102:1102-11