Acetylcholinesterase inhibitor therapy mitigates hypertension in lupus mice

Chronic inflammation is linked to elevated blood pressure, particularly in systemic lupus erythematosus (SLE), where immune dysregulation, hypertension, and renal injury are prevalent. Neural regulation of the immune system helps resolve inflammation, but impaired neuroimmune communication, particularly through reduced activity of the cholinergic anti-inflammatory pathway, may worsen inflammation-driven hypertension. Here, we investigated the effects of long-term systemic administration of the acetylcholinesterase inhibitor, galantamine, which is known to enhance neuroimmune communication and the cholinergic anti-inflammatory pathway, on blood pressure, inflammation and renal injury in SLE mice. Female NZBWF1 mice, a well-established model of SLE, were administered either galantamine (3 mg/kg/day) or saline for 14 consecutive weeks via subcutaneous minipumps and were compared with age-matched and similarly treated NZW control mice. Long-term galantamine treatment improved survival, lowered blood pressure, reduced renal injury markers including urinary albumin, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL), and decreased renal fibrosis in female mice with SLE. Circulating levels of soluble TNFR1 (sTNFR1), a marker of systemic inflammation and mediator involved in the pathogenesis of cardiovascular disease, were reduced in galantamine-treated SLE mice. Galantamine treatment also reduced splenic CD19+ B cells and kidney CD8+ T cells in SLE mice. Boosting the cholinergic anti-inflammatory pathway with acetylcholinesterase inhibitors such as galantamine alleviates pathological attributes in SLE including hypertension, inflammation and renal injury, potentially by modulating B and T cells in the spleen and kidney.