Leptin Antagonism Attenuates Hypertension in a Rodent Model of Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that predominately affects women and is associated with high rates of hypertension and cardiovascular disease. SLE is characterized by B and T lymphocyte dysfunction and altered cytokine production, including elevated levels of the adipocytokine leptin. Leptin has various immunomodulatory properties, including promoting the expansion of proinflammatory T lymphocytes as well as the proliferation and survival of B cells. Because B and T lymphocytes have been implicated in the development of autoimmune‐associated hypertension by our laboratory, we hypothesized that leptin antagonism would attenuate hypertension and renal injury in an experimental model of SLE. To test this hypothesis, 28 week old female SLE (NZBWF1, n=27) and control (NZW, n=25) mice were administered 3 mg/kg of murine leptin superantagonist (LA) or vehicle (0.2% NaHCO3, pH 8.0) every 48 hours for four weeks. At the conclusion of the study, immune cell populations in the peripheral blood were analyzed using flow cytometry. The percentages of CD45R+ B lymphocytes were not significantly different between vehicle and LA‐treated SLE mice (17.4±3.0% SLE‐vehicle vs. 11.7±1.9% SLE‐LA, p=0.1). Similarly, there were no significant changes in CD3+CD4+or CD3+CD8+T cells; however, double negative T cells (CD3+CD4−CD8−) were significantly decreased in SLE mice administered LA as compared to vehicle treated SLE mice (25.1±2.0% SLE‐vehicle vs. 16.4±2.9% SLE‐LA, p=0.03). Increased numbers of these proinflammatory T cells have been previously shown in both patients with SLE and in the NZBWF1 mouse. Mean arterial pressure (MAP; mmHg), measured in conscious mice by carotid artery catheter, was higher in SLE mice than in control mice (115±4 mmHg Controlvehicle vs. 131±2 mmHg SLE‐vehicle, p=0.01), and treatment with LA decreased blood pressure in SLE mice (SLE‐LA: 121±3 mmHg; p=0.03 vs. SLE‐vehicle). Urinary albumin excretion, a marker of renal injury, was assessed by ELISA at the conclusion of the study. Albumin excretion was increased in SLE mice (0.064±0.01 mg/day Control‐vehicle vs. 20.7±9.7 mg/day SLE‐vehicle, p=0.12), but urinary albumin remained elevated in SLE mice administered LA (16.4±6.8 mg/day, p=0.96 vs. SLE‐vehicle). An additional indicator of renal injury, B and T lymphocyte infiltration, was assessed by flow cytometry. SLE mice had significantly higher levels of renal CD45+B cells and CD3+T cells as compared to control mice, but SLE mice treated with LA had lower percentages of renal CD3+T cells as compared to SLE‐vehicle treated mice (2.7±0.6% SLE‐vehicle vs. 1.3±0.2% SLE‐LA, p=0.04). In conclusion, these data suggest that leptin plays a pathogenic role in the development of hypertension in SLE, in part by promoting the expansion of inflammatory T cells and the infiltration of T cells into the kidneys.Support or Funding InformationResearch supported by: VA Merit Award BX002604‐01A2 to MJR, NIH P01HL051971 and P20GM104357 to UMMC‐Department of Physiology and Biophysics, and NIH NHLBI F32HL137393 to EBT.