Caroline Gusson Shimoura , Cassandra Y. Stubbs , Sarika Chaudhari , Viet Q. Dinh , Keisa W. Mathis
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Female </span></span><em>NZBWF1/J</em> (SLE) mice and <em>NZW/LacJ</em> mice (controls, labeled as <em>NZW</em><span><span> throughout) received bilateral microinjections of pAAV-hSyn-hM3D(Gq)-mCherry or control </span>virus<span><span> 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, </span>mean arterial pressure (MAP; mmHg) was increased in SLE mice compared to </span></span><em>NZW</em><span><span> 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, </span>interstitial fibrosis, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) compared to </span><em>NZW</em> mice. Selective DMV neuronal activation reduced albumin excretion rate, glomerulosclerosis, interstitial fibrosis, and NGAL in SLE mice but not <em>NZW</em> 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.</p></div>","PeriodicalId":55410,"journal":{"name":"Autonomic Neuroscience-Basic & Clinical","volume":"250 ","pages":"Article 103129"},"PeriodicalIF":3.2000,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeted stimulation of the vagus nerve reduces renal injury in female mice with systemic lupus erythematosus\",\"authors\":\"Caroline Gusson Shimoura , Cassandra Y. Stubbs , Sarika Chaudhari , Viet Q. Dinh , Keisa W. 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引用次数: 0
摘要
在以高血压、炎症、肾损伤和自主神经异常为特征的系统性红斑狼疮(SLE)小鼠模型中,迷走神经的药理刺激已被证明可以抑制炎症并降低血压。本研究旨在利用设计物药物特异性激活的设计物受体(DREADDs)在迷走神经背侧运动核(DMV)水平直接刺激迷走神经,以确定是否有类似的保护作用并确认机制。雌性NZBWF1/J (SLE)小鼠和NZW/LacJ小鼠(对照组,全部标记为NZW)在31周龄时接受双侧微量注射pAAV-hSyn-hM3D(Gq)-mCherry或对照病毒进入DMV。经过两周的恢复和病毒转染,DREADD激动剂氯氮平- n -氧化物(CNO;3 mg/kg)皮下注射,再持续14天。35周时,平均动脉压(MAP;与NZW小鼠相比,SLE小鼠的mmHg升高,但DMV神经元的选择性激活并未显著改变两组小鼠的MAP。与NZW小鼠相比,SLE小鼠的肾损伤指标包括白蛋白排泄率(μg/d)、肾小球硬化指数、间质纤维化、中性粒细胞明胶酶相关脂钙素(NGAL)和肾损伤分子-1 (KIM-1)。选择性DMV神经元激活降低SLE小鼠的白蛋白排泄率、肾小球硬化、间质纤维化和NGAL,但NZW小鼠没有。综上所述,这些数据表明,通过DREADD选择性激活DMV内的神经元可以保护肾脏,这表明迷走神经介导的通路在SLE肾损伤的进展中起着重要作用。
Targeted stimulation of the vagus nerve reduces renal injury in female mice with systemic lupus erythematosus
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.
期刊介绍:
This is an international journal with broad coverage of all aspects of the autonomic nervous system in man and animals. The main areas of interest include the innervation of blood vessels and viscera, autonomic ganglia, efferent and afferent autonomic pathways, and autonomic nuclei and pathways in the central nervous system.
The Editors will consider papers that deal with any aspect of the autonomic nervous system, including structure, physiology, pharmacology, biochemistry, development, evolution, ageing, behavioural aspects, integrative role and influence on emotional and physical states of the body. Interdisciplinary studies will be encouraged. Studies dealing with human pathology will be also welcome.