摘要
背景:Elabela(ELA)是一种最近确定的apelin受体激动剂,对心脏发育至关重要,但其生物学和治疗潜力尚不清楚。在人类中,在胚胎干细胞,诱导多能干细胞,肾脏,心脏和血管中检测到ELA转录物。 ELA通过apelin(APJ)受体促进体外血管生成,放松鼠主动脉血管和减轻体内高血压。 APJ受体当与其原始配体apelin结合时,发挥外周血管舒张和正性收缩作用,在体内赋予心脏保护作用。 方法:本研究首先评估正常和患病大鼠中的内源性ELA表达,然后表征腺相关病毒血清型9(AAV9)载体的长期ELA基因递送对Dahl盐敏感性大鼠(DS)的心肌功能的影响高盐饮食3个月以上。 结果:内源性ELA主要在肾脏中表达,特别是在肾收集管细胞中,并且不受疾病的影响。大鼠ELA通过单次静脉内注射通过AAV9载体在心脏中过表达。 ELA治疗的动物显示出血压升高的延迟发作。在高盐饮食之前,在给予AAV9-ELA载体的大鼠中观察到分数钠和氯化物排泄的减少。在高盐饮食三个月后,ELA保留肾小球结构,减少肾纤维化和抑制肾脏中纤维化相关基因的表达。 结论:ELA在大鼠肾收集管中组成型表达。持续的AAV-ELA表达可以为高血压和肾重塑提供潜在的长期治疗。
关键词: Elabela,高血压,APJ,肾纤维化,DS,AAV。
Current Gene Therapy
Title:Sustained ELABELA Gene Therapy in High-salt Diet-induced Hypertensive Rats
Volume: 16 Issue: 5
关键词: Elabela,高血压,APJ,肾纤维化,DS,AAV。
摘要: Background: Elabela (ELA) is a recently identified apelin receptor agonist essential for cardiac development, but its biology and therapeutic potential are unclear. In humans, ELA transcripts are detected in embryonic stem cells, induced pluripotent stem cells, kidney, heart and blood vessels. ELA through the apelin (APJ) receptor promotes angiogenesis in vitro, relaxes murine aortic blood vessels and attenuates high blood pressure in vivo. The APJ receptor when bound to its original ligand, apelin, exerts peripheral vasodilatory and positive inotropic effects, conferring cardioprotection in vivo.
Methods: This study initially assessed endogenous ELA expression in normal and diseased rats and then characterized the effects of long-term ELA gene delivery by adeno-associated virus serotype 9 (AAV9) vectors on cardiorenal function in Dahl salt-sensitive rats (DS) on a high-salt diet over 3 months. Results: Endogenous ELA was predominantly expressed in the kidneys, especially in the renal collecting duct cells and was not affected by disease. Rat ELA was overexpressed in the heart via AAV9 vector by a single intravenous injection. ELA-treated animals showed delayed onset of blood pressure elevation. Prior to high-salt diet, a reduction in the fractional sodium and chloride excretion was observed in rats given the AAV9-ELA vector. After three months on a high-salt diet, ELA preserved glomerular architecture, decreased renal fibrosis and suppressed expression of fibrosis-associated genes in the kidneys. Conclusion: ELA is constitutively expressed in renal collecting ducts in rats. Sustained AAV-ELA expression may offer a potential long-term therapy for hypertension and renal remodeling.Export Options
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Cite this article as:
Sustained ELABELA Gene Therapy in High-salt Diet-induced Hypertensive Rats, Current Gene Therapy 2016; 16 (5) . https://dx.doi.org/10.2174/1566523217666161121111906
DOI https://dx.doi.org/10.2174/1566523217666161121111906 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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