Peripheral Blood Mononuclear Cells from Patients with Systemic Lupus Erythematosus Induce Salt Sensitivity of Blood Pressure in Humanized Mice

Abstract

Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular disease (CVD), even in normotensive people. Systemic lupus erythematosus (SLE) is also a risk factor for CVD and hypertension. SLE and CVD are on the rise, and it is not known if this is attributable to the increased dietary salt in the modern diet and SSBP. Isolevuglandins (IsoLGs) adduct self-proteins forming neoantigens in antigen presenting cells (APC) to activate T cells and produce cytokines that promote sodium retention, kidney damage, salt sensitivity of blood pressure, and SLE. We hypothesized that high salt intake increases both blood pressure and the proinflammatory milieu in mice humanized with the immune cells of patients with SLE. We humanized female NSG/MHCI/MHCII−/− immunodeficient mice with peripheral blood mononuclear cells (PBMCs) isolated from patients with SLE (n=5) and controls without autoimmune disease (n=4). The blood pressure was measured with radiotelemetry, immune phenotyping was performed with flow cytometry, and vascular reactivity was assessed in mesenteric arteries using wire myography after two weeks of a 4% high salt diet. High salt treatment significantly increased systolic blood pressure in lupus mice compared to the controls (135.5 vs. 123.8 mmHg, p=0.014). APC infiltration (macrophages, monocytes, dendritic cells), their activation (CD86) and proinflammatory markers (IL-23 p19, TNF-alpha), and oxidative stress (Isolevuglandins, Nox2) were significantly higher in the kidneys of lupus mice. Moreover, the signaling molecule p-STAT3 was significantly higher in myeloid cells in the kidneys of lupus mice. The classical monocyte and proinflammatory markers were significantly elevated in the spleen lymphocytes, and proinflammatory markers were increased in the kidney, spleen, and aorta in lupus mice. These mice exhibited vascular dysfunction (p<0.05), suggesting reduced vascular compliance. We measured urine albumin and found that lupus mice tended to excrete more albumin than the controls (17.24 vs. 25.89 μg/ml p=0.142), suggesting greater kidney injury. In conclusion, our findings suggest that immune cells from patients with SLE, in response to high salt intake, increase blood pressure and the proinflammatory milieu in the kidney, aorta, and spleen; impair vascular compliance; and worsen albuminuria in immunodeficient mice. 1R01HL144941-01A1 1R03HL155041 23CDA1053072. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.