CD14 and Salt-Sensitive Hypertension

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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. We recently discovered a novel anti-hypertensive mechanism that is mediated by Cluster of Differentiation 14 (CD14) and enhanced in females relative to males. CD14 is a co-receptor with Toll Like Receptor 4 (TLR4). Interestingly, the expression of CD14 in leukocytes and level of plasma CD14 protein are increased in cardiovascular disease and hypertension in humans. We propose that CD14 signaling in macrophages in the kidney opposes the effects of TLR4 and leads to the attenuated release of free radicals and the proinflammatory cytokine Il-1β, blunted T cell activation, and attenuated salt-sensitive hypertension. This project is based upon our unique (and somewhat surprising) observation that genetic deletion of CD14, which is upregulated in macrophages in the kidney of Dahl Salt-Sensitive (SS) rats fed high salt, leads to increased release of the proinflammatory cytokine Il-1β and reactive oxygen species. Remarkably, we observed that female Dahl SS rats lacking CD14 (SSCD14-/-) exhibit amplified salt-sensitive hypertension and renal damage compared to wild type littermates. Further study demonstrated that the effects of CD14 deletion are dependent on hematopoietic cells, amplified in females, and eliminated in rats lacking phagocytic NADPH oxidase 2 (NOX2). These exciting data indicate an unexpected, sex-dependent role of CD14 in the development of salt-sensitive hypertension and renal damage. This proposal will test the hypothesis that the anti-hypertensive effects of CD14 in macrophages in the kidney lead to decreased activation of T cells in the kidney, attenuated salt-sensitive hypertension, and decreased renal end-organ damage. The hypothesis will be addressed in three specific aims. Aim 1 will address the hypothesis that the protective effects of CD14 against salt-sensitive hypertension and associated renal damage involve inhibition of TLR4-mediated signaling in macrophages. Aim 2 will address the hypothesis that elevated NOX2 in macrophages mediate elevated blood pressure in Dahl SS rats fed high salt, an effect attenuated in females by CD14 and amplified in males by TLR4. Aim 3 will address the hypothesis that the pro-hypertensive effects of TLR4 and the anti-hypertensive effects of CD14 are mediated by corresponding changes in pressure natriuresis-diuresis and intrarenal hemodynamics in a process dependent upon free radicals released from NOX2 in macrophages and T cells. The proposal employs in vitro and in vivo approaches to address the hypothesis using unique, genetically-engineered rat strains developed for this grant, novel immune cell transfer approaches, and state-of-the art methodology to assess hemodynamic variables in conscious rats.