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(Hypertension. 2008;52:1134.)
© 2008 American Heart Association, Inc.

Original Articles

Dietary Salt Activates an Endothelial Proline-Rich Tyrosine Kinase 2/c-Src/Phosphatidylinositol 3-Kinase Complex to Promote Endothelial Nitric Oxide Synthase Phosphorylation

From the Division of Nephrology (W.-Z.Y., K.A., P.W.S.), Department of Medicine, and Department of Physiology and Biophysics (P.W.S.), University of Alabama at Birmingham; and the Department of Veterans’ Affairs Medical Center (P.W.S.), Birmingham, Ala.

Correspondence to Paul W. Sanders, Division of Nephrology/Department of Medicine, 642 Lyons-Harrison Research Building, 1530 Third Ave, S, University of Alabama at Birmingham, Birmingham, AL 35294-0007. E-mail psanders{at}uab.edu

Although many laboratories have shown that dietary NaCl (salt) intake increases NO production in rodents and humans, the mechanism has not been uncovered. In the present study, pharmacological and dominant-negative strategies were used to show that feeding a formulated diet containing increased amounts of salt to young male Sprague-Dawley rats induced the formation of an endothelial cell-signaling complex that contained proline-rich tyrosine kinase 2, c-Src (also known as pp60^c-src), and phosphatidylinositol 3-kinase. In the setting of a high-salt diet, proline-rich tyrosine kinase 2 served as the scaffold for c-Src–mediated phosphatidylinositol 3-kinase activation. Phosphatidylinositol 3-kinase was the upstream activator of protein kinase B (Akt), which was responsible for phosphorylation of the rat endothelial isoform of NO synthase at S1176 and thereby promoted the increase in NO production. The combined findings illustrated the crucial role for a proline-rich tyrosine kinase 2–signaling complex in the endothelial response to salt intake.

Key Words: NO • cell signaling • cell biology • animal models of human disease

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