The overall goal of this grant proposal is to advance the understanding of the pathophysiology of salt-sensitive hypertension by investigating the role of renal 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). 11beta-HSDs are critical controllers of local levels of active glucocorticoids. Alterations of 11beta-HSDs that cause local excess of glucocorticoids in the kidney or other tissues (e.g., transgenic over-expression of the glucocorticoid-regenerating isoform 11beta-HSDI) result in hypertension. However, the importance of 11beta- HSDs in common forms of hypertension remains unclear. The Dahl salt-sensitive (SS) rat is a widely used model of human salt-sensitive hypertension. The consomic SS-13BN rat is genetically highly similar to SS, but has substantially reduced blood pressure salt-sensitivity. Previous studies from this laboratory found that 11beta-HSDI was over-expressed in the renal medulla (a kidney region critical for long-term blood pressure regulation) of SS compared to SS-13BN when rats were exposed to a high-salt diet. The proposed studies will test the hypothesis that dysregulation of renal medullary 11beta-HSD1 contributes to the development of salt-sensitive hypertension in SS rats. Studies are designed to: 1) characterize the expression and localization of 11beta-HSDI and related genes in SS and SS-13BN rats; 2) utilize in vivo small interfering RNA techniques to selectively suppress the expression of renal medullary 11beta-HSDI, which is not achievable with common pharmacological inhibitors, and examine the effect of such suppression on salt-induced hypertension in chronically instrumented SS rats; 3) begin to examine the functional mechanism for the role of 11beta-HSDI in salt-sensitive hypertension by investigating the effect of 11beta-HSDI suppression on renal tubular segmental fluid reabsorption in SS rats using micropuncture. Preliminary data has demonstrated the feasibility of the proposed studies and appeared to support the hypothesis. These studies will combine innovative molecular analysis/manipulation and functional assessment in genetically defined or modified animal models. The results are expected to elucidate a novel aspect of the pathophysiology of salt- sensitive hypertension and to provide potential new targets for prevention and treatment of hypertension.
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