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Chronic Vagus Nerve Stimulation Attenuates Renal Inflammation in Autoimmune‐Induced Hypertension
Author(s) -
Pham Grace S,
Fairley Amber S,
Maloy Charles I,
Mathis Keisa W
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.962.7
Subject(s) - medicine , cholinergic , inflammation , endocrinology , vagus nerve stimulation , vagus nerve , lupus nephritis , stimulation , efferent , immunology , disease , afferent
Chronic renal inflammation has been implicated in the pathogenesis of hypertension, which identifies the autoimmune disease systemic lupus erythematosus (SLE) as a compelling disease model due to its key features of lupus nephritis and prevalent hypertension. The cholinergic anti‐inflammatory pathway is an endogenous, vagally‐mediated neuroimmune pathway that, when impaired, may influence the development of chronic inflammation. While stimulation of the cholinergic anti‐inflammatory pathway attenuates inflammation in models of sepsis and other inflammatory diseases, it is not clear if the pathway is impaired in SLE, nor whether its stimulation is protective in SLE. We hypothesized that pharmacological activation of the cholinergic anti‐inflammatory pathway at the level of the vagus nerve would decrease renal inflammation and therefore blood pressure in a murine model of SLE hypertension. Initially, female SLE ( NZWF1 ) and control ( NZW ) mice were administered the efferent vagal stimulant, CNI‐1493 (Semapimod hydrochloride; 8 mg/kg IP) or saline twice per week for 4 weeks starting at 30 weeks of age. SLE mice had 1143±439% (p<0.001), 74±24% (p=0.006), and 225±124% (p=0.009) higher renal cortical expression of the inflammatory mediators TNF‐α, IL‐1, and high mobility group box (HMGB)‐1 than controls (n=3–5/group). CNI‐1493 reduced TNF‐α, IL‐1 and HMGB‐1 by 13±11% (p=NS), 29±11% (p=0.05), and 42±5% (p=NS) in SLE mice. We continued to test our hypothesis by stimulating the efferent vagus via administration of the centrally‐acting acetylcholinesterase inhibitor, galantamine (GAL; 4mg/kg IP), or saline to SLE and control mice for 14 consecutive days starting at 32 weeks of age. SLE mice had 502±332% (p=0.037) and 345±35% (p=0.002) higher renal cortical expression of TNF‐α and IL‐6 than controls (n=2–4/group). GAL lowered TNF‐α and IL‐6 by 56 ±16% (p=NS) and 61±2% (p=0.006) in SLE mice. Interestingly, when we assessed whether mean arterial pressure (MAP) was altered following vagal stimulation and subsequent reduction of renal cytokines, we found that MAP (n=3–6/group) was higher in SLE mice compared to controls (143±11 vs. 116±4; p=0.003) and that both CNI‐1493 and GAL prevented the rise in MAP in SLE mice (130±4 and 135±7, respectively). These preliminary results suggest that chronic vagal nerve stimulation attenuates renal inflammation and therefore prevents the development of hypertension in SLE. Ultimately, delineating the role of the cholinergic anti‐inflammatory pathway in SLE could support further investigation into the pathway's role in other autoimmune diseases, as well as essential hypertension, which has recently been shown to arise from an inflammatory etiology. Support or Funding Information Studies supported by the AHA (#14SDG18320033) and UNTHSC (Faculty Pilot Grant)