Csk regulates blood pressure by controlling the synthetic pathways of aldosterone

Background: Blood pressure is regulated by a network of diverse physiological pathways. The C-terminal Src kinase (CSK) locus (15q24) is associated with blood pressure in various ethnic groups. It was recently reported that Csk insufficiency increases blood pressure through Src. The mechanisms of hypertension in Csk ^+/− mice are examined further in this study. Methods and Results: To identify a causal component responsible for hypertension in Csk ^+/− , the heart rate was measured by electrocardiogram and plasma volume by Evans blue dilution. Plasma volume increased in Csk ^+/− compared with wild-types, while the heart rate did not change. Plasma sodium and aldosterone levels rose consistently in Csk ^+/− vs. wild-types, and spironolactone, a mineralocorticoid receptor antagonist, reduced blood pressure. The amounts of Sgk1 and Na ⁺ /K ⁺ -ATPase (NKA) increased in the kidney of Csk ^+/− compared with wild-types. It was also found that Cyp11b2 (aldosterone synthase) was upregulated in the adrenal glands of Csk ^+/− , and that Csk was enriched in the zona glomerulosa of adrenals, the major site of aldosterone production in the normal mouse. Conclusions: The results of the present study identify a physiological pathway by which blood pressure is regulated, in which the insufficiency of Csk induces aldosterone production with zonal specificity in the adrenal glands, increasing sodium reabsorption and plasma volume and thus resulting in hypertension.