SUMMARY
Hypertension is a primary modifiable risk factor for cardiovascular, cerebrovascular, and renal disease, and is
the largest individual contributing factor to disease and mortality in the world. Salt-sensitive hypertensive
individuals, who comprise 30-50% of the hypertensive population, have greater mortality than subjects with salt-
resistant hypertension and exhibit renal end-organ damage. Immunity and inflammation are implicated in
hypertension and renal damage in humans and experimental animal, but the mechanisms triggering immunity in
hypertension are not understood. Dietary components other than salt can also play an important role in the
development of cardiovascular disease and hypertension. Interestingly, an inverse relationship has been
demonstrated between plant protein intake and blood pressure, ultimately associating health benefits with
greater plant protein consumption. We recently discovered a novel link between dietary protein intake, immune-
activation, and hypertension in the Dahl Salt-Sensitive (SS) rat, a rodent model of human disease.
The experiments in this proposal will test the overarching hypothesis that free radical production from
phagocytic NOX2 in infiltrating CD4+ T cells in the kidney of Dahl SS leads to an inappropriate elevation of renal
vascular resistance (RVR), a reduction in glomerular filtration rate (GFR), the retention of sodium, and the further
development of hypertension following high salt feeding. As a corollary to this hypothesis, we propose that the
microbial metabolite carnitine, released by consumption of animal-based diets, upregulates NOX2 in T cells and
amplifies salt-sensitive hypertension. In contrast, the metabolite propionate, released from consumption of grain-
based diets, downregulates NOX2 and diminishes the full amplitude of salt-sensitive hypertension. The
hypothesis will be addressed in two specific aims. Aim 1 will address the mechanisms whereby alterations in
dietary protein source affect the release of metabolites from the gut microbiota and determine the influence of
these metabolites on NOX2 in T cells and in the development of salt-sensitive hypertension. Aim 2 will address
the role of phagocytic NOX2 in CD4+ T cells as a mediator of inappropriately increased renal vascular resistance
and the development of salt-sensitive hypertension in Dahl SS by adoptive transfer of either wild type or NOX2-
deficient CD4+ T cells into SS rats lacking T cells. This work will transform the understanding of salt-sensitive
hypertension by utilizing novel animal models and approaches to demonstrate the mechanisms whereby dietary
protein intake modifies immune mechanisms which serve to amplify disease severity. These studies should
reveal new paradigms and provide insight with the potential to transform clinical/therapeutic approaches for the
treatment of salt-sensitive hypertension.