Name: improved renal denervation mitigated hypertension induced by angiotensin ii infusion
Uploaded: 2022-05-26T13:00:00
Description: Watch this Scientific Journal Video about Improved Renal Denervation Mitigated Hypertension Induced by Angiotensin II Infusion at JoVE.com

本研究得到了国家自然科学基金（81770420）、上海市科学技术委员会（20140900600）、上海市老年临床医学重点实验室（13dz2260700）、上海市临床重点专科（shslczdzk02801）和复旦大学附属华东医院老年冠状动脉疾病中心的支持。

所有动物实验程序均符合实验动物护理和使用的相关伦理指南（NIH出版物编号85-23，2011年修订），并得到复旦大学附属华东医院动物研究委员会的批准。将14周龄雄性C57BL/6小鼠（28-30g）随机分为4组：假鼠组、假+Ang II组、RDN组、RDN+Ang II组，每组n = 6。所有动物均在24±1°C的温度受控室中在特定封闭的无病原体条件下饲养，光照/黑暗循环12小时，并随意获得标准啮齿动物食物和水。
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<ol>
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L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+controlled+trial+of+renal+denervation+for+resistant+hypertension.">A controlled trial of renal denervation for resistant hypertension.</a> The New England Journal of Medicine. 370 (15), 1393-1401 (2014).</li><li>Kjeldsen, S. E., Narkiewicz, K., Burnier, M., Oparil, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Renal+denervation+achieved+by+endovascular+delivery+of+ultrasound+in+RADIANCE-HTN+SOLO+or+by+radiofrequency+energy+in+SPYRAL+HTN-OFF+and+SPYRAL-ON+lowers+blood+pressure.">Renal denervation achieved by endovascular delivery of ultrasound in RADIANCE-HTN SOLO or by radiofrequency energy in SPYRAL HTN-OFF and SPYRAL-ON lowers blood pressure.</a> Blood Press. 27 (4), 185-187 (2018).</li><li>B&#246;hm, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Efficacy+of+catheter-based+renal+denervation+in+the+absence+of+antihypertensive+medications+(SPYRAL+HTN-OFF+MED+Pivotal):+a+multicentre,+randomised,+sham-controlled+trial.">Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial.</a> The Lancet. 395 (10234), 1444-1451 (2020).</li><li>Azizi, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Endovascular+ultrasound+renal+denervation+to+treat+hypertension+(RADIANCE-HTN+SOLO):+a+multicentre,+international,+single-blind,+randomised,+sham-controlled+trial.">Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial.</a> The Lancet. 391 (10137), 2335-2345 (2018).</li><li>Kandzari, D. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effect+of+renal+denervation+on+blood+pressure+in+the+presence+of+antihypertensive+drugs:+6-month+efficacy+and+safety+results+from+the+SPYRAL+HTN-ON+MED+proof-of-concept+randomised+trial.">Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial.</a> The Lancet. 391 (10137), 2346-2355 (2018).</li><li>Townsend, R. 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E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Renal+denervation+prevents+heart+failure+progression+via+inhibition+of+the+renin-angiotensin+system.">Renal denervation prevents heart failure progression via inhibition of the renin-angiotensin system.</a> Journal of the American College of Cardiology. 72 (21), 2609-2621 (2018).</li><li>Wang, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Renal+denervation+attenuates+progression+of+atherosclerosis+in+apolipoprotein+E-deficient+mice+independent+of+blood+pressure+lowering.">Renal denervation attenuates progression of atherosclerosis in apolipoprotein E-deficient mice independent of blood pressure lowering.</a> Hypertension. 65 (4), 758-765 (2015).</li><li>Chen, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Renal+denervation+mitigates+atherosclerosis+in+ApoE-/-+mice+via+the+suppression+of+inflammation.">Renal denervation mitigates atherosclerosis in ApoE-/- mice via the suppression of inflammation.</a> American Journal of Translational Research. 12 (9), 5362-5380 (2020).</li><li>Wang, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Renal+denervation+promotes+atherosclerosis+in+hypertensive+apolipoprotein+E-deficient+mice+infused+with+Angiotensin+II.">Renal denervation promotes atherosclerosis in hypertensive apolipoprotein E-deficient mice infused with Angiotensin II.</a> Frontiers in Physiology. 8, 215 (2017).</li><li>Eriguchi, M., Tsuruya, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Renal+sympathetic+denervation+in+rats.">Renal sympathetic denervation in rats.</a> Methods in Molecular Biology. 1397, 45-52 (2016).</li><li>Thukkani, A. K., Bhatt, D. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Renal+denervation+therapy+for+hypertension.">Renal denervation therapy for hypertension.</a> Circulation. 128 (20), 2251-2254 (2013).</li><li>Zhang, Y. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=NAD(+)+administration+decreases+microvascular+damage+following+cardiac+ischemia/reperfusion+by+restoring+autophagic+flux.">NAD(+) administration decreases microvascular damage following cardiac ischemia/reperfusion by restoring autophagic flux.</a> Basic Research in Cardiology. 115 (5), 57 (2020).</li><li>Wang, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Long-term+renal+sympathetic+denervation+ameliorates+renal+fibrosis+and+delays+the+onset+of+hypertension+in+spontaneously+hypertensive+rats.">Long-term renal sympathetic denervation ameliorates renal fibrosis and delays the onset of hypertension in spontaneously hypertensive rats.</a> American Journal of Translational Research. 10 (12), 4042-4053 (2018).</li><li>Lu, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Subcutaneous+Angiotensin+II+infusion+using+osmotic+pumps+induces+aortic+aneurysms+in+mice.">Subcutaneous Angiotensin II infusion using osmotic pumps induces aortic aneurysms in mice.</a> Journal of Visualized Experiments: JoVE. 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自症状性HTN-3试验7，25的阴性结果发表以来，RDN是否可以降低血压一直存在争议。然而，几项临床试验和动物实验已经证明了RDN对高血压人和动物的积极有效结果9，10，11，12，13，14，15，16</...

高血压是全世界主要的慢性心血管疾病。不受控制的高血压可能会损害靶器官并导致心力衰竭、中风和慢性肾脏疾病1，2，3。1991年至2007年间，中国的高血压患病率从20%上升到31%。在最近修订高血压诊断标准（130/80 mmHg）4后，中国成人高血压患者人数可能会翻一番。高血压可以通过药物控制，然而，大约20%的患者无法控制他们的高血压，即使以最大耐受剂量接受至少三种抗高血压药物（包括一种利尿剂），这可能导致耐药性高血压的发展5。
肾交感神经去神经支配（RDN）已被证明是高血压的潜在治疗方法。2009年，Krum及其同事首次报告了使用RDN进行难治性高血压治疗。结果发现经皮肾动脉消融术可有效引起患者持续性血压降低6.然而，Symplicity Hypertension 3 （HTN-3） 试验的失败阻碍了 RDN 7 的应用，使 RDN成为一种有争议的疗法。然而，RDN的前景尚未被排除。最近的临床试验，包括RADIANCE-HTN SOLO，SPYRAL HTN-OFF MED/ON MED和SPYRAL HTN-OFF MED Pivotal已经证实了RDN对高血压8，9，10，11，12的疗效。因此，需要进行更详细的机理研究来探索RDN的影响。
本研究的总体目的是证明如何修改小鼠中的RDN以产生更简单，更稳定的手术。大量的实验研究了RDN的各种方法，如血管内冷冻消融，体外超声和化学或神经毒素在不同动物模型中的局部应用13，14，15，16，17。使用苯酚化学消融生成的RDN模型是研究交感神经激活对高血压发病机制的成熟实验模型。该模型是通过使用棉签10%苯酚/乙醇溶液对肾交感神经进行化学腐蚀而产生的18。一方面，常规RDN潜在地抑制肾交感神经活性，从而减少肾素分泌和钠重吸收，并增加肾血流量。另一方面，它抑制肾素-血管紧张素-醛固酮系统19。因此，RDN对高血压有有益的作用。然而，化学消融生成的RDN模型缺乏消融标准和消融时间，实验过程的细节尚不清楚。此外，没有可用的技术报告。在本报告中，我们描述了一种使用称重纸在血管紧张素II（Ang II）诱导的C57BL / 6小鼠高血压中用苯酚生成RDN模型的手术方案。我们用含有苯酚的称量纸包裹肾动脉并统一消融时间，这有助于建立更可重复、更可靠的 RDN 模型。该实验模型旨在评估RDN对高血压的影响。

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Angiotensin II</td>
			<td>Sangon Biotech</td>
			<td>CAS:4474-91-3</td>
			<td>To make a hypertensive animol model</td>
		</tr>
		<tr>
			<td>Anti-Tyrosine Hydroxylase antibody</td>
			<td>Abcam</td>
			<td>ab137869</td>
			<td>To evaluate the expression of TH of renal nerves</td>
		</tr>
		<tr>
			<td>Blood Pressure Analysis</td>
			<td>Visitech Systems</td>
			<td>BP-2000</td>
			<td>Measure the blood pressure of mice</td>
		</tr>
		<tr>
			<td>Mini-osmotic pump</td>
			<td>DURECT Corporation</td>
			<td>CA 95014</td>
			<td>To fill with Angiotensin II</td>
		</tr>
		<tr>
			<td>Norepinephrine ELISA Kit</td>
			<td>Abcam</td>
			<td>ab287789</td>
			<td>to measure renal norepinephrine levels</td>
		</tr>
		<tr>
			<td>Phenol</td>
			<td>Sangon Biotech</td>
			<td>CAS:108-95-2</td>
			<td>Damage the renal sympathetic nerve</td>
		</tr>
		<tr>
			<td>Weighing paper</td>
			<td>Sangon Biotech</td>
			<td>F512112</td>
			<td>To destroy renal nerve with weighing paper immersed with phenol; https://www.sangon.com/productDetail?productInfo.code=F512112.&#160;</td>
		</tr>
	</tbody>
</table>

improved renal denervation mitigated hypertension induced by angiotensin ii infusion

近年来，肾交感神经去神经支配（RDN）对血压的益处已在大量临床试验中得到证实。然而，RDN对高血压的调节机制仍然难以捉摸。因此，在小鼠中建立更简单的RDN模型至关重要。在这项研究中，将充满血管紧张素II的渗透迷你泵植入14周龄的C57BL / 6小鼠中。植入微型渗透泵一周后，使用苯酚对小鼠的双侧肾动脉进行改良的RDN程序。给予年龄性别匹配的小鼠盐水并作为假组。在基线时测量血压，随后每周测量血压，持续21天。然后，收集肾动脉，腹主动脉和心脏，使用H&E和Masson染色进行组织学检查。在这项研究中，我们提出了一种简单、实用、可重复和标准化的RDN模型，可以控制高血压，缓解心脏肥大。该技术可以去神经支配周围肾交感神经，而不会造成肾动脉损伤。与以前的模型相比，改进的RDN有助于研究高血压的病理生物学和病理生理学。

统计学 所有数据均表示为平均值±标准偏差。单因素方差分析用于具有三个或更多条件的实验，然后进行Bonferroni事后检验以比较各个组。将等于或小于 0.05 的 p 值视为显著性。使用商业软件进行所有统计分析。
RDN后，Ang II引起的血压升高减弱 在输注Ang II后1周观察到收缩压（SBP）显着升高。与Sham + Ang II组相比，RDN + Ang II组在RDN手术后21天显示SBP?...

Watch this Scientific Journal Video about Improved Renal Denervation Mitigated Hypertension Induced by Angiotensin II Infusion at JoVE.com

Improved Renal Denervation Mitigated Hypertension Induced by Angiotensin II Infusion

在这里，我们提出了由血管紧张素II输注诱导的高血压小鼠肾交感神经去神经支配（RDN）的方案。该程序可重复，方便，并允许研究RDN对高血压和心脏肥大的调节机制。

改善肾去神经支配缓解血管紧张素II.诱导的高血压

The benefits of renal sympathetic denervation (RDN) on blood pressure have been proved in a large number of clinical trials in recent years. However, the ...

肾交感神经去神经支配是高血压的潜在治疗方法，已被许多临床试验证明。该技术去神经支配自由流动的肾神经，而不会造成肾动脉损伤。此外，它是一个简单、关键、可重复和标准化的模型。演示该程序的是我实验室的实验室助理Ming Wang。首先用70%乙醇对手术台进行消毒，然后将加热垫温度调节到37摄氏度。手术前，对所有手术器械进行消毒，包括显微手术剪刀、细直钳、细弯钳、止血钳、无菌纱布和121摄氏度的称量纸30分钟。麻醉14周大的雄性C57BKL / 6小鼠后，用剃须刀去除背部的毛发，然后在眼睛上涂抹兽医软膏以防止干燥。将鼠标放在背部位置的手术台上。用聚维酮碘擦拭剃光区域，然后用 70% 乙醇擦拭三片。使用无菌手术刀刀片，在前腿肩胛骨上方垂直于耳朵后面的尾巴做一个一厘米的切口。接下来，使用无菌止血器在皮肤下建立皮下隧道，并为泵创建一个口袋。轻轻地将装满血管紧张素II的渗透泵插入口袋，确保有足够的自由空间缝合伤口，而不会拉伸皮肤。用中断的6-0 Vicryl缝合线缝合肌肉，并用中断的4-0尼龙缝合线闭合皮肤。然后用聚维酮碘擦拭伤口部位。将所有手术器械放入灭菌器中10秒钟，并在手术之间更换无菌手套。监视鼠标，直到它完全恢复。在第一周内每天至少两次密切监测和观察伤口愈合情况，随后每天一次，包括发红、肿胀和感染。如果小鼠在血管紧张素II输注期间死亡，请立即进行解剖。在基线和血管紧张素II输注后每周测量血压，在有意识的小鼠中用尾袖体积描记法。血管紧张素II输注一周后，选择血压升高的小鼠并记录其体重。选择体重最低为24克的动物进行肾去神经支配手术。接下来，用剃须刀去除麻醉小鼠腹部的毛发，然后将鼠标放在手术台上。保持腹部向上并用胶带固定四肢。用聚维酮碘消毒腹部皮肤，然后用70%乙醇擦拭三片。做一个两厘米的腹侧中线腹部切口后，用浸泡在37摄氏度盐水中的纱布拉回肠道，露出左肾动脉。小心但直截了当地，使用弯曲的镊子将脂肪从肾动脉上解剖开。使用无菌锋利的剪刀，将称重纸切成与肾动脉大小相同的矩形。一次切几张称量纸以保持形状相同。将称量纸浸入 10% 苯酚乙醇溶液中至少 30 秒。覆盖左肾动脉表面，用称重纸包裹血管两分钟。使用纱布保护周围组织，避免称量纸接触肾脏和肠道。对右肾动脉重复相同的程序。手术后，将肌肉重新定位到初始位置，并以中断的缝合模式用6-0 Vicryl缝合线关闭腹膜，然后用中断的4-0尼龙缝合线闭合皮肤。监测所有小鼠，直到完全恢复。在血管紧张素II输注后一周观察到收缩压显着升高。肾交感神经去神经支配（RDN）血管紧张素II组在RDN手术后21天与假血管紧张素II组相比，收缩压显着降低。在RDN手术后两周，假手术组和RDN组之间没有观察到显着差异。苏木精和肾交感神经和肾动脉的伊红染色见此处。4组未见肾动脉内膜增厚。与假细胞组、碎片化和裂缝核相比，两个RDN组均观察到神经内组织的消化和肿胀。神经束免疫组织化学显示，RDN组和RDN血管紧张素II.组酪氨酸羟化酶表达均低于假神经束组。与神经支配肾相比，正常血压和高血压组去神经支配肾中去神经支配肾的肾皮质去甲肾上腺素含量显着降低。马森染色显示，各组腹主动脉内膜介质无显著增加。此处显示了不同组中心肌的代表性图像。RDN治疗通过减少间质纤维化和心肌细胞大小来改善血管紧张素II.输注诱导的心脏肥大。在手术过程中，不要将苯酚接触除肾动脉以外的周围组织，因为它可能导致肠梗阻、腹部感染和肾动脉狭窄。该方法可以建立标准化的RDN模型，以帮助研究控制高血压的机制。该技术的未来应用有助于扩大强调高血压和心脏肥大过程的途径。

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SCIENTISTS IN ACTION

A Laser-induced Mouse Model of Chronic Ocular Hypertension to Characterize Visual Defects

激光诱导的慢性高眼压表征视觉缺陷的小鼠模型

Glaucoma, frequently associated with elevated intraocular pressure (IOP), is one of the leading causes of blindness. We sought to establish a mouse model ...

科研

医学

Tibial Nerve Transection - A Standardized Model for Denervation-induced Skeletal Muscle Atrophy in Mice

胫骨神经切断术 - 一个标准化的模型失神经诱导小鼠骨骼肌

The tibial nerve transection model is a well-tolerated, validated, and reproducible model of denervation-induced skeletal muscle atrophy in rodents. ...

Assessment of Vascular Function in Patients With Chronic Kidney Disease

血管功能在慢性肾脏疾病的评估

Patients with chronic kidney disease (CKD) have significantly increased risk of cardiovascular disease (CVD) compared to the general population, and this ...

Early Detection of Drug-Induced Renal Hemodynamic Dysfunction Using Sonographic Technology in Rats

大鼠使用超声技术药物引起的肾血流动力学障碍的早期检测

The kidney normally functions to maintain hemodynamic homeostasis and is a major site of damage caused by drug toxicity. Drug-induced nephrotoxicity is ...

Murine Kidney Transplant Technique

小鼠肾脏移植技术

The first mouse kidney transplant technique was published in 19731 by the Russell laboratory. Although it took some years for other labs to become ...

Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice

使用渗透皮下血管紧张素Ⅱ输液泵诱导主动脉瘤小鼠

Osmotic pumps continuously deliver compounds at a constant rate into small animals.  This article introduces a standard protocol used to induce aortic ...

Novel Approach for Simultaneous Recording of Renal Sympathetic Nerve Activity and Blood Pressure with Intravenous Infusion in Conscious, Unrestrained Mice.

清醒、无拘无束的小鼠静脉输液同时记录肾交感神经活动和血压的新方法。

Renal sympathetic nerves contribute significantly to both physiological and pathophysiological phenomena. Evaluating renal sympathetic nerve activity ...

Shunt Surgery, Right Heart Catheterization, and Vascular Morphometry in a Rat Model for Flow-induced Pulmonary Arterial Hypertension

分流手术，右心导管，血管形态计量学在大鼠模型中的流量引起的肺动脉高压

In this protocol, PAH is induced by combining a 60 mg/kg monocrotalin (MCT) injection with increased pulmonary blood flow through an aorto-caval shunt ...

Improved Registration of 3D CT Angiography with X-ray Fluoroscopy for Image Fusion During Transcatheter Aortic Valve Implantation

经导管主动脉瓣植入术中 X 线透视 3D CT 血管造影的改进与影像融合

The fusion of 3D anatomical models derived from high-fidelity pre-interventional computed tomography angiography (CTA), and x-ray (XR) fluoroscopy to ...

Left Atrial Stenosis Induced Pulmonary Venous Arterialization and Group 2 Pulmonary Hypertension in Rat

左心房狭窄致大鼠肺静脉动脉化及第2组肺动脉高压

The mechanism of mitral stenosis-induced pulmonary venous arterialization and group 2 pulmonary hypertension (PH) is unclear. There is no rodent model of ...