Abstract P290: Unilateral Cervical Vagotomy Protects Against Renal Injury and Hypertension in a Mouse Model of Lupus Hypertension

Abstract

Chronic renal inflammation has been implicated in hypertension. The vagus nerve controls inflammation by immunoregulatory mechanisms like the hypothalamic-pituitary-adrenal axis and the cholinergic anti-inflammatory pathway. It is not clear whether changes in vagal activity affect inflammation downstream in the kidney. We hypothesized that decreasing vagal neurotransmission would impede these anti-inflammatory mechanisms, exacerbate renal inflammation and promote hypertension. To study this, we used a mouse model of systemic lupus erythematosus (SLE) that develops hypertension after the onset of autoimmunity. Female SLE ( NZBWF1) and control (NZW) mice received right unilateral cervical vagotomy (Vx) or sham surgery (n=4-6/group) and 3 weeks later had catheters implanted to measure blood pressure. Sham-operated SLE mice had elevated plasma double-stranded DNA autoantibodies (3.8 x 10 5 ± 1.3 x 10 4 vs. 1.1 x 10 5 ± 5.0 x 10 4 activity units; all p<0.05 unless otherwise noted), a hallmark of the disease; enlarged spleens (239.1 ± 80.4 vs. 124.1 ± 11.4 mg); and an elevated splenic CD3+CD4+ T cell population (flow cytometry; 21.9 ± 2.1 vs. 14.6 ± 2.8%) relative to controls. Vagotomy did not alter disease severity (3.2 x 10 5 ± 3.5 x 10 4 ; p = 0.20), but prevented splenomegaly (119.7 ± 24.2 mg) and reduced CD3+CD4+ T cells (14.7 ± 0.7) in SLE mice. SLE mice trended toward higher renal cortical TNF-α than controls (3.5 x 10 6 ± 1.7 x 10 6 vs. 7.6 x 10 4 ; normalized to total protein; p = 0.22), although SLE/Vx mice had lower concentrations than SLE/sham mice (4.9 x 10 5 ± 1.3 x 10 5 vs. 3.5 x 10 6 ± 1.7 x 10 6 ). SLE mice had higher albumin excretion rates (AER) than controls (1.2 x 10 4 ± 3.6 x 10 3 vs. 2.0 x 10 1 ± 4.8 μg/day) and Vx decreased AER in SLE mice (1.2 x 10 4 ± 3.6 x 10 3 ). SLE mice were hypertensive compared to controls (158 ± 10 mmHg vs. 108 ± 4 mmHg) and vagotomy protected SLE mice from hypertension (133 ± 4). In sum, these data counter our initial hypothesis—unilateral vagotomy reduced renal inflammation and halted the progression of SLE hypertension. The vagus nerves have myriad functions and perhaps other neuroimmune interactions compensate for the ligation of one nerve. Future studies will investigate whether our findings may be due to long-term adaptation following unilateral vagotomy.