The persistent prevalence of hypertension as a clinical disease and the non- eradication of its target organ complications despite therapy defines the clinical mandate to investigate the molecular genetics of hypertension. The elucidation of underlying genotypes for each hypertension subtype could facilitate the mechanistic analysis of the complexities of hypertension due to interactive environmental factors, genetic background and gene interactions, thus providing a critical tool towards the directive prevention and intervention of hypertension. Cognizant of the complexities of hypertension, an integrated multidisciplinary approach with a rational prioritization scheme is necessary. This proposal focuses on the salt-sensitive hypertensive subtype relevant to hypertension in African Americans wherein the disease is characterized by greater prevalence, morbidity and mortality. Mechanistic analysis requires the investigation of a strategic animal model: the Dahl salt-sensitive (S) hypertensive and Dahl salt resistant (R) normotensive rat strains. Since the applicants have identified a mutant Q276Lalphal Na,K-ATPase and mutant renal-specific bumetanide-sensitive Na,K,Cl-cotransporter in Dahl S rats compared with Dahl R rats, they hypothesize that functional abnormalities in alpha1 Na,K-ATPase and/or Na,K,Cl- cotransporter contribute to the development of salt-sensitive hypertension and/or its renal complications in the Dahl S strain singly or interactively.
The specific aims prioritized are: I) to determine the genetic contribution of the mutant alpha1 Na,K-ATPase and the mutant Na,K,Cl- cotransporter genes to the salt-sensitive hypertension phenotype of Dahl S rats as single, additive or multiplicative hypertension genes thus elucidating a critical aspect for the definition of one or both as hypertension genes; II) to determine the biologic consequences of the mutant alphal Na,K- ATPase in strategic transgenic Dahl S rat models in order to delineate its mechanistic role in hypertension; III) to determine the molecular and functional characteristics of Dahl S and Dahl R Na,K,Cl-cotransporter variants, thus assessing the potential mechanistic physiologic role in the Dahl salt-sensitive rat hypertensive phenotype. The successful completion of this research program will define a) the alphal Na,K-ATPase as bona fide hypertension gene; b) the status of the Na,K,Cl-cotransporter as a candidate hypertension gene; c) will establish the infrastructure for the study of future candidate hypertension genes in the Dahl S rat hypertensive model; and d) will pave the way for the direct assessment of the role of these hypertension genes in the development of hypertension in selective human populations.
