? ? Hypertension and hypertensive renal disease are a common conditions that together create an extremely high disease burden. Work from this laboratory showed that dietary salt intake plays a key role in end-organ injury and suggested a new paradigm involving a central role of the endothelium in production of transforming growth factor-?1 (TGF-?1) in response to changes in salt intake and a modulating role for endothelium-derived NO in TGF-?1 production in the vessel wall and glomerulus. The findings emphasized the concept that plasticity of the endothelium plays an integral role in maintaining vascular tone and renal function in response to changes in dietary salt intake. The working hypotheses of this renewal application are that dietary salt intake modulates endothelial cell signaling events involved in the production of bioactive molecules, including TGF- ?1 and NO, and that impaired NO production facilitates TGF- ?1activity in salt-sensitive hypertension. The first specific aim will determine the signal transduction events involved in the up-regulation of TGF- ?1 by dietary salt and will focus on protein kinase C (PKC) and proline-rich tyrosine kinase 2 (Pyk2, also known as RAFTK, CAK- ? and CADTK).
Aim 2 will determine the mechanism of salt-induced active TGF- ?1 production and the mechanism by which NO inhibits endothelial cell production of TGF- ?1.
Aim 3 will define the post-translational modifications of the endothelial isoform of nitric oxide synthase (NOS3) involved in NO production in response to increased salt intake and the mechanism of impaired NOS3 function in S rats. The long-term goal is to determine the functional adaptation and consequences of salt intake on endothelial cell function in the vasculature and the kidney. By defining the signal transduction pathway in endothelial cells and the interrelationship between NO and TGF- ?1, this application will provide novel insights into events that initiate injury in the arterioles and kidney associated with hypertension and changes in salt intake and potentially provide new approaches to inhibition of TGF- ?1 function independently of inhibition of the renin-angiotensin-aldosterone axis. ? ? PROJECT NARRATIVE ? ? The long-term goal is to determine the functional adaptation and consequences of salt intake on endothelial cell function in the vasculature and the kidney. By defining the signal transduction pathway in endothelial cells and the inter-relationship between NO and TGF- ?1, this application will provide novel insights into events that initiate injury in the arterioles and kidney associated with hypertension and changes in salt intake and potentially provide new approaches to inhibition of TGF- ?1 function independently of inhibition of the renin-angiotensin-aldosterone axis. ? ? ?
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