A physiologic and molecular characterization of an animal model of salt-sensitive arterial hypertension

Abstract

Over 60 million Americans are afflicted with essential hypertension--a potentially dangerous elevation of arterial blood pressure. Although the etiology of this disorder is largely unknown, two factors are of undisputed importance: a permissive genetic background and the prolonged ingestion of salt in amounts greater than 50 meq/day. The salt-sensitive (S) and salt resistant (R) rats developed by Lewis Dahl provide a convenient genetic model to address hypertension experimentally and have been used extensively to study various physiologic systems mediating salt-sensitive arterial hypertension. The studies to be presented were based on the proposition that the comparative physiology of the Dahl rat model of hypertension might suggest new pathways toward identifying genes responsible for the hypertensive phenotype, and that such are worthy of exploration. As the renal handling of sodium and water plays a primary role in the pathogenesis of Dahl hypertension, subtractive and differential hybridization methods were used to identify kidney messages expressed at a higher rate in either the R normotensive or S hypertensive rat. Messenger RNA expression was addressed quantitatively by dot blot, northern blot, and RNase protection assays in the two strains of rat for recombinant phage appearing to bear differentially expressed messages. Likewise, expression of messages for a number of known genes whose physiologic role suggests an involvement in hypertension were also evaluated. After screening {dollar}{lcub}>{rcub}10\sp4{dollar} plaques (from both S and R kidney cDNA libraries) by different experimental paradigms, over fifty messages appeared to be differentially expressed. A second round of quantitative dot blot analysis narrowed the field to six clones showing significant differences in expression between S and R rats. These latter clones have been sequenced resulting in the identification of several previously undescribed cDNAs. The temporal nature of their expression in the kidneys of S and R rats following salt loading has been partially evaluated. Future work will characterize the genes encoding these differentially expressed cDNAs and examine their linkage to hypertension in segregating populations.