NADPH oxidase-mediated NLRP3 Inflammasome Activation in Dahl Salt-Sensitive Hypertension

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Project Summary Nearly half of the ~70 million Americans with hypertension exhibit salt-sensitivity, with the prevalence disproportionately greater in African Americans. Our observations in the Dahl Salt-Sensitive (SS) rat model parallel the same elevation in blood pressure, albuminuria, and infiltration of T lymphocytes and macrophages into the kidney that is observed in salt-sensitive human hypertension. However, the mechanisms that mediate the infiltration of immune cells into the kidney and activate adaptive immunity in hypertension are unknown. The NLRP3 inflammasome is a novel multiprotein complex that plays a critical role in innate immune system initiation, especially during sterile inflammation, and may be the missing link between innate and adaptive immune mechanisms in salt-sensitive hypertension. The present studies will test the general hypothesis that redox activation of the NLRP3 inflammasome in the SS kidney mediates the initiation of the adaptive immune response and the subsequent infiltration of T lymphocytes that amplify salt-induced hypertension and renal damage. To test this hypothesis, two specific aims are proposed. AIM 1 will test the hypothesis that the expression and activation of the NLRP3 inflammasome will increase in Dahl SS rat kidneys during the transition from a low (LS, 0.4% NaCl) to high salt (HS, 4.0% NaCl) diet, and test whether pharmacological inhibition of NLRP3 inflammasome activation attenuates salt-induced hypertension and renal damage in Dahl SS rats. To understand how redox mechanisms contribute to this pathway, AIM 2 will test the hypothesis that reactive oxygen species (ROS) mediate NLRP3 inflammasome activation in Dahl SS rat kidneys, and test the contribution of ROS from the renal parenchyma versus infiltrating immune cells to NLRP3 inflammasome activation through total body irradiation/bone marrow transfer (TBI/BMT) studies. This proposal will be the first to study the production of ROS in the activation of NLRP3 inflammasomes in Dahl SS rats and the first to link this novel innate immune mechanism to salt-induced initiation of the adaptive immune response, the infiltration of T lymphocytes into the kidney, leading to the eventual progression of hypertension and renal injury. Completion of these studies will establish a clear role for the NLRP3 inflammasome and will make new breakthroughs in defining key factors that initiate the immune system cascade in salt-sensitive hypertension. These findings will have the potential to make big contributions in the development of new therapeutics. Through the discovery of more refined targets, earlier intervention strategies and more effective therapies, these studies have the power to positively impact a large population, with the ultimate goal of one day overcoming hypertension and related cardiovascular diseases.