Hypertension affects one-third of Americans of which approximately half are termed salt-sensitive. Previous work in our laboratory has implicated a significant role for the immune system in potentiating the hypertensive and kidney damage phenotypes which occur in the Dahl Salt-Sensitive (SS) rat. An RNAseq based transcriptomic experiment on medullary tissue from SS rats fed either a low or high salt diet demonstrated an upregulation of molecules involved in the innate immune response including Cluster of Differentiation 14 (CD14). CD14 has been associated with hypertension in various human and animal studies, but mechanistic studies have not been previously performed. Preliminary studies in SS rats with a genetic knockout of CD14 (SSCD14-/-) show an exacerbation of the salt-sensitive hypertensive and kidney damage phenotypes. In addition, isolated peritoneal macrophages from wild type and knockout animals showed an increase ability to produce IL-1? in response to lipopolysaccharide stimulation in the SSCD14-/-, indicative of a more pro-inflammatory phenotype. This proposal will address the overall hypothesis that CD14 is a negative regulator of the inflammatory response in macrophages during development of salt-sensitive hypertension and renal damage. This will be addressed in two specific aims.
Specific Aim 1 test the hypothesis that a null mutation of CD14 will amplify salt-sensitive hypertension and renal damage in the Dahl SS rat. Experiments in this aim will use SSCD14+/+ and SSCD14- /- animals on a low- (0.4% NaCl) and high- (4.0%NaCl) salt diet and will assess the development of hypertension and kidney damage, as well as the number and type of infiltrating immune cells.
Specific Aim 2 will interrogate the function of the altered immune system in the SSCD14-/- animal and will test the hypothesis that CD14 activation is a regulator of macrophage inflammatory phenotype. Infiltrating macrophages will be assessed in respect to M1/M2 polarization and gene expression patterns.
Cardiovascular disease remains as the number one cause of death in the United States. The role the immune system plays in the development of hypertension, the number one risk factor for cardiovascular disease, may provide additional avenues for screening and treatment. Investigators have shown that both the innate and adaptive immune system contribute to the pathophysiology of salt-sensitive hypertension and this proposal will test the hypothesis that macrophages, an important immune system cell, are activated in hypertension by a process, which involves the molecule Cluster of Differentiation 14 (CD14).