THE ALPHA-1 NA,K-ATPASE GENE IS A SUSCEPTIBILITY HYPERTENSION GENE INTHE DAHL SALT-SENSITIVE(HSD) RAT

Despite the prevalence of essential hypertension, its underlying genet ic basis has not been elucidated due to the complexities of its determ inants. To identify a hypertension susceptibility gene, we used an app roach that integrates molecular, transgenic, and genetic analysis usin g Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats ascertained for genotype and phenotype. To determine the role of the Dahl S Q276L alpha 1 Na,K-ATPase gene variant, we developed transgenic Dahl S rats bearing the Dahl R wild-type (wt) oil Na,K-ATPase cDNA directed by th e cognate wt promoter region, Tg[wt alpha 1]. Transgenic Dahl S rats e xhibited less salt-sensitive hypertension, less hypertensive renal dis ease, and longer life span when compared with non-transgenic Dahl S co ntrols. Total chromosome 2 linkage analysis of F2(SXR) male rats detec ts cosegregation of the cll Na,K-ATPase locus with salt-sensitive hype rtension. These data support the alpha 1 Na,K-ATPase gene as a suscept ibility gene for salt-sensitive hypertension in the Dahl S rat model, and provide the basis for the study of the alpha 1 Na,K-ATPase locus i n human hypertension.