Usa, Kristie

Dietary salt intake has significant effects on arterial blood pressure and the development of hypertension. Mechanisms underlying salt-dependent changes in blood pressure remain poorly understood. The goal of the present study was to utilize urine samples from the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial and a targeted metabolomic approach to identify associations of urinary metabolites with blood pressure phenotypes on low- or high-sodium intake. We examined urinary levels of metabolites in 103 participants of the DASH-Sodium trial after 30 days on a defined diet containing high sodium (targeting 150 mmol sodium intake per day) or low sodium (50 mmol sodium per day). Systolic or diastolic pressure was 10 or more mmHg higher on the high-sodium intake in 51 of the 103 participants. Targeted chromatography/mass spectrometry analysis was performed in 24-h urine samples for 10 metabolites related to the tricarboxylic acid cycle and 47 amino metabolites. Urinary metabolite levels improved the prediction of classification of blood pressure salt-sensitivity based on race, age and sex. Random forest and generalized linear mixed model analyses identified significant (false discovery rate <0.05) associations between 24 h excretions of β-aminoisobutyric acid, cystine, citrulline, homocysteine and lysine and systolic blood pressure and between cystine and diastolic blood pressure. The differences of 24 h excretion of homocysteine between low- and high-sodium intakes were significantly associated with the differences in diastolic blood pressure. These associations were significant with or without considering demographic factors. Treatment with β-aminoisobutyric acid significantly attenuated high-salt-induced hypertension in Dahl salt-sensitive rats. These findings support the presence of new mechanisms of blood pressure regulation involving metabolic intermediaries.

The Dahl salt-sensitive rat is a widely used model of human salt-sensitive forms of hypertension. The kidney plays an important role in the pathogenesis of Dahl salt-sensitive hypertension, but the molecular mechanisms involved remain a subject of intensive investigation. Gene expression profiling studies suggested that 11β-hydroxysteroid dehydrogenase type 1 might be dysregulated in the renal medulla of Dahl salt-sensitive rats. Additional analysis confirmed that renal medullary expression of 11β-hydroxysteroid dehydrogenase type 1 was downregulated by a high-salt diet in SS-13BN rats, a consomic rat strain with reduced blood pressure salt sensitivity, but not in Dahl salt-sensitive rats. 11β-Hydroxysteroid dehydrogenase type 1 is known to convert inactive 11-dehydrocorticosterone to active corticosterone. The urinary corticosterone/11-dehydrocorticosterone ratio as well as urinary excretion of corticosterone was higher in Dahl salt-sensitive rats than in SS-13BN rats. Knockdown of renal medullary 11β-hydroxysteroid dehydrogenase type 1 with small-interfering RNA attenuated the early phase of salt-induced hypertension in Dahl salt-sensitive rats and reduced urinary excretion of corticosterone. Knockdown of 11β-hydroxysteroid dehydrogenase type 1 did not affect blood pressure in SS-13BN rats. Long-term attenuation of salt-induced hypertension was achieved with small hairpin RNA targeting renal medullary 11β-hydroxysteroid dehydrogenase type 1. In summary, we have demonstrated that suppression of 11β-hydroxysteroid dehydrogenase type 1 expression in the renal medulla attenuates salt-induced hypertension in Dahl salt-sensitive rats.