Pharmacological stimulation of the vagus nerve has been shown to suppress inflammation and reduce blood pressure in a murine model of systemic lupus erythematosus (SLE) that is characterized by hypertension, inflammation, renal injury and dysautonomia. The present study aims to directly stimulate vagal nerves at the level of the dorsal motor nucleus of the vagus (DMV) using designer receptors exclusively activated by designer drugs (DREADDs) to determine if there is similar protection and confirm mechanism. Female NZBWF1/J (SLE) mice and NZW/LacJ mice (controls, labeled as NZW throughout) received bilateral microinjections of pAAV-hSyn-hM3D(Gq)-mCherry or control virus into the DMV at 31 weeks of age. After two weeks of recovery and viral transfection, the DREADD agonist clozapine-N-oxide (CNO; 3 mg/kg) was injected subcutaneously for an additional 14 days. At 35 weeks, mean arterial pressure (MAP; mmHg) was increased in SLE mice compared to NZW mice, but selective activation of DMV neurons did not significantly alter MAP in either group. SLE mice had higher indices of renal injury including albumin excretion rate (μg/day), glomerulosclerosis index, interstitial fibrosis, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) compared to NZW mice. Selective DMV neuronal activation reduced albumin excretion rate, glomerulosclerosis, interstitial fibrosis, and NGAL in SLE mice but not NZW mice. Together, these data indicate that selective activation of neurons within the DMV by DREADD protects the kidney suggesting an important role of vagus-mediated pathways in the progression of renal injury in SLE.

在以高血压、炎症、肾损伤和自主神经功能障碍为特征的系统性红斑狼疮 (SLE) 小鼠模型中，迷走神经的药物刺激已被证明可以抑制炎症并降低血压。本研究旨在使用专门由设计药物激活的设计受体（DREADD）直接刺激迷走神经背运动核（DMV）水平的迷走神经，以确定是否存在类似的保护并确认机制。雌性NZBWF1/J (SLE) 小鼠和NZW/LacJ小鼠（对照，全文标记为NZW ）在 31 周龄时在 DMV 中接受双侧显微注射 pAAV-hSyn-hM3D(Gq)-mCherry 或对照病毒。恢复和病毒转染两周后，皮下注射 DREADD 激动剂氯氮平 N-氧化物（CNO；3 mg/kg），持续 14 天。 35 周时，与NZW小鼠相比，SLE 小鼠的平均动脉压（MAP；mmHg）有所增加，但选择性激活 DMV 神经元并没有显着改变两组的 MAP。与NZW小鼠相比，SLE小鼠具有更高的肾损伤指数，包括白蛋白排泄率（μg/天）、肾小球硬化指数、间质纤维化、中性粒细胞明胶酶相关脂质运载蛋白（NGAL）和肾损伤分子1（KIM-1）。选择性DMV神经元激活降低了SLE小鼠的白蛋白排泄率、肾小球硬化、间质纤维化和NGAL，但不降低NZW小鼠。总之，这些数据表明 DREADD 选择性激活 DMV 内的神经元可以保护肾脏，表明迷走神经介导的通路在 SLE 肾损伤进展中发挥重要作用。