Salt Sensitivity of Blood pressure (SSBP) and Autoimmune Lupus (SLE)

Vanderbilt University Medical Center, Nashville TN

Investigators

Abstract

Abstract: Both salt-sensitivity of blood pressure (SSBP) and autoimmune systemic lupus erythematosus (SLE) are risk factors for cardiovascular disease (CVD). SLE and CVD are on the rise, and it is not known if this is attributed to the increased dietary salt in the modern diet and SSBP. Our research indicates that sodium enters antigen presenting cells (APCs) via the epithelial sodium channel (ENaC), and this is regulated by the Serum/Glucocorticoid regulated Kinase 1 (SGK1). This results in activation of NADPH oxidase, leading to formation of products of lipid oxidation known as isolevuglandins (IsoLGs). IsoLGs adduct to self-proteins forming neoantigens in APCs to activate T cells and produce cytokines that promote sodium retention, kidney damage, endothelial dysfunction, hypertension and SLE. Scavenging of IsoLGs using 2-hydroxybenzylamine (2-HOBA) improves vascular function, reduces immune cell activation in hypertension, and anti-dsDNA antibodies in the SLE mice. We have rigorously phenotyped people with hypertension for SSBP using an inpatient salt loading and depletion protocol and found that activation of APCs including monocytes via IsoLGs changes according to salt- loading/depletion and blood pressure changes in salt-sensitive but not salt-resistant individuals. This was associated with similar dynamic changes in downstream genes including the inflammasomes, SGK1, and the ENaC-δ subunit using single cell CITE-Seq analysis followed by extensive protein expression and functional validation. Humans with SLE have increased sodium in tissues and this is associated with increased APC activation via IsoLGs. These studies suggest that sodium activates these cells and that IsoLGs might mediate salt SSBP. The goal of this proposal is to determine if IsoLG-induced immune cell activation mediates endothelial dysfunction in SSBP and if SLE contributes to SSBP. In Aim 1 we will determine if scavenging of IsoLGs alleviates the SSBP phenotype in humans. In Aim 2, we will determine if IsoLG-adduct accumulation in monocytes we observe in SSBP is paralleled by endothelial accumulation of IsoLG-adducts, inflammatory markers and evidence of ROS formation, and that this is associated with vascular dysfunction as assessed by flow mediated vasodilatation (FMD). In Aim 3, we will determine if immune cells from SLE subjects induce hypertension and salt-sensitivity in humanized mice and to examine mechanisms. We have exciting preliminary data that adoptive transfer of immune cells from lupus patients induces albuminuria and increases the hypertensive response to salt feeding in recipient NSG/MHCI/MHCII-/- mice immunodeficient mice. We will salt feed SLE1.2.3 mice and assess SLE severity, SSBP immune activity and renal function. In addition, we will treat with 2-HOBA and determine if this prevents the detrimental effects of high salt in SLE mice. These studies promise to be highly impactful in advancing the field of how salt impacts health and disease.