ABSTRACT Hypertension is a leading cause of global mortality and is the primary modifiable risk factor for renal and cardiovascular disease. In 50% of patients with essential hypertension, blood pressure increases in response to salt. Despite this, the mechanisms underlying salt-sensitive hypertension remain poorly understood. Our studies in Dahl salt-sensitive (SS) rats have shown that proteinuria is indicative of the initiation of salt-sensitive hypertension, whereas renal inflammation is involved in the amplification of the disease. To date, the link between proteinuria and renal inflammation in salt-sensitive hypertension has not been elucidated, moreover the mechanisms by which renal T-cells amplify salt-sensitive hypertension have not been fully determined. Based on our previous work and preliminary data we hypothesize that exposure of the renal tubule to excess protein (proteinuria) causes its “inflammatory activation” and the release of the chemokines CCL4 and CCL5. We anticipate that this tubular production of CCL4 and CCL5 initiates renal inflammation by attracting CCR1 and CCR5 positive immune cells to regions of injury. We hypothesize that once in the kidney, T-cells amplify hypertension by promoting renal injury, sodium retention and oxidative stress. Therefore, we predict that antagonism of CCR1 and CCR5 may provide a novel treatment for hypertension. Our hypothesis is supported by our compelling preliminary data indicating: 1) overexpression of CCL4 and CCL5 and their receptors, CCR1 and CCR5 in the hypertensive kidney of SS rats, 2) localization of CCL4 and CCL5 in the renal tubules of salt- sensitive rats fed high-salt for 12-days and 3) increased p67phox (indicative of oxidative stress) and col1a1 (indicative of fibrosis) in the kidneys of SS rats with T-cells relative to those without, in the absence of differences in blood pressure. This proposal has two Specific Aims: 1. Determine the role of the chemokines CCL4 and CCL5 and their receptors CCR1 and CCR5 in the initiation of renal inflammation during the development of salt- sensitive hypertension. 2. Use a unique pressure-matching approach in salt-sensitive (SSCD247+/+) and T-cell deficient (SSCD247-/-) rats to isolate the pathological effects of renal T-cells, in vivo, on renal function.