My long-term goal is to utilize the techniques of Molecular Biology to investigate genes of possible importance in genetic hypertension. This work is being carried out in genetically hypertensive rats and will provide insight into the genetic mechanisms controlling blood pressure. I have found remarkable structural differences in the renin genes of the Dahl salt.sensitive (S) and Dahl salt.resistant (R) rats. Most of these differences are located at the 5' end of renin genes where the promoter and regulatory elements are located. In addition, the elevation in blood pressure in response to high sodium diet was directly associated with the number of S renin-alleles in a given rat's genome as proven by genetic co-segregation analysis in F2 rats. In order to evaluate the function of renin alleles of S and R rats, the effects of the structural differences of the renin alleles in Dahl rats an renin gene expression and/or renin protein structure will be determined. Renal renin mRNA from both strains of Dahl rats will be characterized and compared in order to look for differences in mRNA between strains which may result from gene structural differences. Functional analysis of promoters of R and S renin alleles will be performed to determine if the structural alterations in the 5' ends of these genes cause any functional changes. We will also examine and identify transacting factors influencing renin gene expression in order to determine whether or not the same factors are functioning in the S and R rats. In addition, we will compare the responses of S and R renin gene expressions to various stimuli which are known to affect renin production, such as converting enzyme inhibition and stimuli involving sodium metabolism such as sodium depletion and sodium loading. We will also characterize transacting factors which are associated with these renin responses. The results obtained from these experiments will provide valuable information of the regulation of renin gene expression and might help us to explain the cause of the cosegregation of S renin alleles with blood pressure increments as observed in our genetic studies.
