Name: a modified two kidney one clip mouse model of renin regulation in renal artery stenosis
Uploaded: 2020-10-26T13:00:00
Description: Watch this Scientific Journal Video about A Modified Two Kidney One Clip Mouse Model of Renin Regulation in Renal Artery Stenosis at JoVE.com

研究得到了NHLBI研究科学家发展补助金（1K01HL135461-01）对JAG的支持。感谢大卫·卡莫纳-贝里奥和伊莎贝尔·阿达尔维-伦吉福的技术援助。

根据美国国立卫生研究院（NIH）指南和美国卫生与公众服务部的范德比尔特大学医学中心（VUMC）动物护理部对小鼠进行饲养和护理。在开始实验之前，所有动物程序都得到了VUMC机构动物护理和使用委员会的批准。
1. 动物准备和解剖
<ol><li>在开始手术前约30分钟打开加热垫的发芽器和水泵。</li>
	<li>用锋利的手术刀切割0.5毫米长的聚氨酯管。取下 0.2 毫米的周长，纵向切开，?...

<ol>
	<li>Kashyap, S., 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=Blockade+of+CCR2+reduces+macrophage+influx+and+development+of+chronic+renal+damage+in+murine+renovascular+hypertension.">Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension.</a> American Journal of Physiology-Renal Physiology. 310 (5), 372-384 (2016).</li><li>Wang, W., 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=Changes+in+inflammatory+biomarkers+after+renal+revascularization+in+atherosclerotic+renal+artery+stenosis.">Changes in inflammatory biomarkers after renal revascularization in atherosclerotic renal artery stenosis.</a> Nephrology Dialysis Transplantation. 31 (9), 1437-1443 (2016).</li><li>Yerram, P., Karuparthi, P. 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O., 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=Inhibition+of+PDE5+Restores+Depressed+Baroreflex+Sensitivity+in+Renovascular+Hypertensive+Rats.">Inhibition of PDE5 Restores Depressed Baroreflex Sensitivity in Renovascular Hypertensive Rats.</a> Frontiers in Physiology. 7, 15 (2016).</li><li>Dias, A. T., 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=Sildenafil+ameliorates+oxidative+stress+and+DNA+damage+in+the+stenotic+kidneys+in+mice+with+renovascular+hypertension.">Sildenafil ameliorates oxidative stress and DNA damage in the stenotic kidneys in mice with renovascular hypertension.</a> Journal of Translational Medicine. 12, 35 (2014).</li><li>Lerman, L. O., Chade, A. 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A., Goldblatt, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Studies+on+Experimental+Hypertension:+XVIII.+Experimental+Observations+on+the+Humoral+Mechanism+of+Hypertension.">Studies on Experimental Hypertension: XVIII. Experimental Observations on the Humoral Mechanism of Hypertension.</a> Bulletin of the New York Academy of Medicine. 18 (7), 459-487 (1942).</li><li>Warner, G. 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=Genetic+deficiency+of+Smad3+protects+the+kidneys+from+atrophy+and+interstitial+fibrosis+in+2K1C+hypertension.">Genetic deficiency of Smad3 protects the kidneys from atrophy and interstitial fibrosis in 2K1C hypertension.</a> American Journal of Physiology-Renal Physiology. 302 (11), 1455-1464 (2012).</li><li>Lorenz, J. 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A., Ichikawa, S., Kurz, K. D., Fowler, W. L., Payne, C. 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肾动脉狭窄是继发性或难治性高血压和肾损伤的重要病因1，29.两个肾脏一夹（2K1C）Goldblatt模型已被用于研究RAS狭窄诱导的肾血管高血压1，17，18，19。以前使用各种动物模型的一些研究表明，肾动脉狭窄是肾素过表达和释放的强大刺激因子，肾损伤<sup class=...

肾动脉狭窄（RAStenosis）是一种棘手的问题，影响约6%的65岁以上人群和高达40%的冠状动脉或外周血管疾病患者1，2。目前对这种疾病的治疗是有限的;因此，迫切需要开发新的疗法来治疗肾血管性高血压或由RAStenosis诱导的抵抗性高血压。肾素血管紧张素醛固酮系统（RAAS）是参与RAS狭窄诱导的高血压或肾血管性高血压发病机制的关键途径3，4。针对 RAAS 的已知疗法（如血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂）可缓解高血压，但需要仔细检查肾衰竭和高钾血症5，6，7。肾素催化RAAS中的速率限制步骤;它将血管紧张素原转化为血管紧张素I。在动脉粥样硬化中，斑块形成导致肾动脉变窄，从而驱动肾素分泌，导致肾血管高血压和肾脏损伤8。许多研究报告了人类肾血管性高血压期间氧化应激水平升高，这与两个肾脏一夹（2K1C）小鼠模型以及其他高血压动物模型2，9，10，11，12，13，14，15，16证实。.RAS狭窄诱发的肾血管性高血压期间肾素表达控制的分子机制尚不清楚，需要进一步研究。
可靠且可重复地概括RAStenosis的实验动物模型对于阐明肾素表达控制的细胞和分子机制以开发新疗法非常重要。2K1C小鼠模型是研究肾血管性高血压发病机制的成熟实验模型17，18，19，20。该模型通过使用夹子17，20，21的肾动脉收缩而生成，因此产生肾动脉阻塞，导致肾素表达增加和高血压17，19，20，21。然而，没有可用的技术报告，其中描述了在动物模型中产生肾动脉狭窄的分步过程。
传统的U形银夹，聚氨酯管和其他夹子已被用于收缩肾动脉以诱导肾动脉狭窄。一些研究表明，夹子的设计和材料对于获得2K1C动物模型的可靠和可重复数据至关重要。根据Lorenz等人的说法，使用传统的U型设计银夹诱导高血压的成功率较低（40-60%）21。由于夹子设计，肾动脉被横向压压，引发一些收缩和更大的概率从肾动脉中移出。银的延展性和延展性可能允许夹子宽度的变化;因此，在小鼠中引起不同的高血压水平。夹子上的二氧化银可引起血管周围炎症、内膜增殖和组织肉芽形成，改变肾动脉直径22。由于用常规U-design银夹获得的高血压水平的可变性，Warner等人和Lorenz等人已经成功地使用圆形设计的聚氨酯管来启动小鼠的肾动脉狭窄，从而产生更可靠和一致的诱导两肾一夹动物模型20，21。
在这份报告中，我们描述了一种手术方案，以在小鼠中产生实验性RAStenosis，使用聚氨酯管来收缩肾动脉。聚氨酯圆形设计袖口是一种更具可重复性，可靠性和低成本的夹子，可在小鼠中产生狭窄。该实验模型的目标是研究和定义肾动脉狭窄期间肾素表达控制的分子和细胞机制。我们通过测量肾素表达和肾损伤标志物中性粒细胞明胶酶相关脂质运载蛋白（N-GAL）来确认RAS狭窄小鼠模型的成功。

<table>
	<tbody>
		<tr>
			<td>Diet Gel</td>
			<td>Clear H2O</td>
			<td>Diet-Gel 76A</td>
			<td>Surgery recovery diet</td>
		</tr>
		<tr>
			<td>EMC Heated Hard pad</td>
			<td>Hallowell</td>
			<td>000A2788B</td>
			<td>Heating pads were used to keep mice warm</td>
		</tr>
		<tr>
			<td>Ethilon Nylon Suture</td>
			<td>Ethicon</td>
			<td>662G</td>
			<td>4-0 (1.5 metric), This suture was used to close the peritoneum, and skin</td>
		</tr>
		<tr>
			<td>Ethilon Nylon Suture</td>
			<td>Ethicon</td>
			<td>2815 G</td>
			<td>8-0 (0.4 metric), This suture was used to close cuff to tie and constrict the artery</td>
		</tr>
		<tr>
			<td>Germinator 500</td>
			<td>Braintree Scientific Inc.</td>
			<td>GER 5287</td>
			<td>Sterilize surgical tools between surgeries</td>
		</tr>
		<tr>
			<td>Ketoprofen</td>
			<td>Zoetis</td>
			<td>Ketofen</td>
			<td>Painkiller</td>
		</tr>
		<tr>
			<td>Polyurethane</td>
			<td>Braintree Scientific Inc.</td>
			<td>MRE-025</td>
			<td>This tube was used to initiate stenosis</td>
		</tr>
		<tr>
			<td>Povidone-iodine antiseptic swabsticks</td>
			<td>Medline</td>
			<td>MDS093901</td>
			<td>It was applied after hair removal and surgery on the skin</td>
		</tr>
		<tr>
			<td>Reflex 7 Clip Applier</td>
			<td>Roboz Surgical Instrument Co</td>
			<td>204-1000</td>
			<td>This clip applier was used to apply clip in case one or more sutures went off</td>
		</tr>
		<tr>
			<td>Sterile towel drapes</td>
			<td>Dynarex</td>
			<td>4410</td>
			<td>It was used as a bedsheet for mice during surgery</td>
		</tr>
		<tr>
			<td>Triple antibiotic ointment</td>
			<td>Medi-First</td>
			<td>22312</td>
			<td></td>
		</tr>
		<tr>
			<td>Water pump</td>
			<td>Stryker</td>
			<td>T/pump Professionals</td>
			<td>Used to warm and circulate water in the heating hard pad to keep mice warm during and post-surgery</td>
		</tr>
	</tbody>
</table>

a modified two kidney one clip mouse model of renin regulation in renal artery stenosis

肾动脉狭窄是冠状动脉或外周血管疾病患者的常见病症，其中肾素血管紧张素醛固酮系统（RAAS）过度活化。在这种情况下，肾动脉变窄，刺激肾素（RAAS中的限速蛋白酶）表达和释放的增加。由此产生的肾素表达升高是肾血管性高血压的已知驱动因素，通常与肾损伤和终末器官损伤有关。因此，人们对开发针对这种情况的新疗法非常感兴趣。肾动脉狭窄中肾素控制的分子和细胞机制尚不完全清楚，需要进一步研究。为了诱导小鼠肾动脉狭窄，开发了一种修饰的2肾1夹（2K1C）Goldblatt小鼠模型。野生型小鼠右肾被冷冻，假手术小鼠用作对照。肾动脉狭窄后，我们确定了肾素表达和肾损伤。收获肾脏，并使用新鲜皮质来确定肾素的蛋白质和mRNA表达。该动物模型是可重复的，可用于研究参与肾血管性高血压和肾损伤的病理生理学反应，分子和细胞途径。

肾动脉收缩增加狭窄肾中的肾素表达，同时抑制对侧肾的表达。狭窄的两个肾一夹（2K1C）或Goldblatt模型诱导肾素表达增加和肾损伤。这被认为是人类单侧肾动脉狭窄的最佳代表性模型。
使用免疫印迹法测量肾素和原脯素（肾素的前体）的表达。数据显示，与对侧肾和假肾相比，狭窄肾中的肾素和原脯素表达增加，表明袖带收缩肾动脉，导致肾灌注改变（图1</s...

Watch this Scientific Journal Video about A Modified Two Kidney One Clip Mouse Model of Renin Regulation in Renal Artery Stenosis at JoVE.com

A Modified Two Kidney One Clip Mouse Model of Renin Regulation in Renal Artery Stenosis

使用聚氨酯管开发改良的2肾1夹（2K1C）Goldblatt小鼠模型以启动肾动脉狭窄，诱导肾素表达增加和肾损伤。在这里，我们描述了准备袖带并将其置于肾动脉上以产生可重复且一致的2K1C小鼠模型的详细程序。

肾动脉狭窄肾素调节的改良双肾单夹小鼠模型

Renal artery stenosis is a common condition in patients with coronary or peripheral vascular disease where the renin angiotensin aldosterone system (RAAS) ...

Research

JoVE Journal

Medicine

Use of a Hanging-weight System for Isolated Renal Artery Occlusion

一个悬重系统使用隔离肾动脉闭塞

In hospitalized patients, over 50% of cases of acute kidney injury (AKI) are caused by renal ischemia 1-3. A recent study of hospitalized patients ...

科研

医学

Mouse Model of Middle Cerebral Artery Occlusion

大脑中动脉闭塞的小鼠模型

Stroke is the most common fatal neurological disease in the United States 1. The majority of strokes (88%) result from blockage of blood vessels in the ...

Modified Technique for Coronary Artery Ligation in Mice

改性技术在小鼠冠状动脉结扎

Myocardial infarction (MI) is one of the most important causes of mortality in humans1-3. In order to improve morbidity and mortality in patients with MI ...

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 ...

Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration

肾缺血再灌注损伤：损伤的小鼠模型和再生

Renal ischaemia reperfusion injury (IRI) is a common cause of acute kidney injury (AKI) in patients and occlusion of renal blood flow is unavoidable ...

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 ...

Mouse Model for Pancreas Transplantation Using a Modified Cuff Technique

应用改良袖套技术的小鼠胰腺移植模型

Mouse models have several advantages in transplantation research, including easy handling, a variety of genetically well-defined strains, and the ...

Assessment of Kidney Function in Mouse Models of Glomerular Disease

小鼠肾小球疾病模型肾脏功能的评价

The use of murine models to mimic human kidney disease is becoming increasingly common. Our research is focused on the assessment of glomerular function ...

Isometric Contractility Measurement of the Mouse Mesenteric Artery Using Wire Myography

用线 Myography 测定小鼠肠系膜动脉的等轴收缩力

The wire myograph technique is used to assess the contractility of vascular smooth muscles in response to depolarization, GPCR agonists/inhibitors and ...

An Efficient Sieving Method to Isolate Intact Glomeruli from Adult Rat Kidney

一种从成年大鼠肾脏中分离完整型肾小球的有效筛分方法

Preservation of glomerular structure and function is pivotal in the prevention of glomerulonephritis, a category of kidney disease characterized by ...