Csk Regulates Blood Pressure by Controlling the Synthetic Pathways of Aldosterone

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 thatCskinsufficiency increases blood pressure through Src. The mechanisms of hypertension inCsk^+/-mice are examined further in this study.

To identify a causal component responsible for hypertension inCsk^+/-, the heart rate was measured by electrocardiogram and plasma volume by Evans blue dilution. Plasma volume increased inCsk^+/-compared with wild-types, while the heart rate did not change. Plasma sodium and aldosterone levels rose consistently inCsk^+/-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 ofCsk^+/-compared with wild-types. It was also found that Cyp11b2 (aldosterone synthase) was upregulated in the adrenal glands ofCsk^+/-, and that Csk was enriched in the zona glomerulosa of adrenals, the major site of aldosterone production in the normal mouse.

The results of the present study identify a physiological pathway by which blood pressure is regulated, in which the insufficiency ofCskinduces aldosterone production with zonal specificity in the adrenal glands, increasing sodium reabsorption and plasma volume and thus resulting in hypertension.