The role of salt in activation of immune system in hypertension

• Grant number: 14/17300-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: February 01, 2015
• End date: July 31, 2015
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Heitor Moreno Junior
• Grantee: Natália Ruggeri Barbaro
• Supervisor: David G. Harrison
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Vanderbilt University (VU), United States
• Associated to the scholarship: 12/23410-7 - Association between metalloproteinase-9 polimorphisms and inflammation on ventricular hypertrophy and vascular stiffness in resistant hypertension, BP.DR

Abstract

Resistant hypertensive patients have unfavorable prognosis attributed to extended time of poor BP control and higher prevalence of target organ damage, including vascular damage. Several factors are involved in resistance to treatment including excessive dietary sodium intake Indeed, RHTN subjects presented higher arterial stiffness compared to normotensive or mild to moderate subjects. Several studies have implicated inflammatory cytokines in the genesis of hypertension, we previously demonstrated that the proinflammatory cytokine IL-1² correlates with arterial stiffness and levels of blood pressure, and is particularly high in patients with resistant hypertension. Also, we found that isoprostane levels, an oxidative stress marker, are associated with endothelial dysfunction in these patients and increased levels of this markers are found in RHTN compared to mild to moderate hypertension and normotension. However, the mechanisms by which inflammatory cells promote hypertension remains unclear. Interestingly, Harrison et al. demonstrated a novel pathway in which Ang II promotes inflammation and ultimately hypertension. They demonstrated that a consequence of reactive oxygen species production is arachidonic acid oxidation and formation of isoketals (isoKs). This is associated with dendritic cell (DCs) accumulation of IsoK adducts and production of IL-6, IL-1² and IL-23. Treatment of DCs with the isoketal scavenger (2-HOBA) inhibits isoketal accumulation, cytokine production by DCs and reduces Ang II-induced hypertension. In parallel, recent data found that salt drives differentiation of inflammatory cells. Thus, we aim to investigate if excess sodium activates immune cells, leading to hypertension and end-organ damage in DOCA-salt hypertension. While in our studies in humans do not allow a causal inference, studies with animal models of hypertension will clarify the role of salt in the activation of the immune system in hypertension. Dendritic cells will be isolated from mice spleen and cultured with media containing 190 mmol/L Na+. We will evaluate the surface expression of co- stimulatory ligands CD80 and CD86 as well as IL-1², IL-6, IL-23 and MMP-9 concentrations in the culture media. In addition, we will adoptively transfer DCs treated to hypertensive animals (DOCA-salt hypertension) and we will evaluate the accumulation of activated cells in the aorta, mesenteric arterioles, and kidney in these animals. (AU)