Human adrenomedullin gene delivery protects against cardiac hypertrophy, fibrosis, and renal damage in hypertensive dahl salt-sensitive rats.
Human adrenomedullin gene delivery protects against cardiac hypertrophy, fibrosis, and renal damage in hypertensive dahl salt-sensitive rats.
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人肾上腺髓质素基因递送可防止高血压达尔盐敏感大鼠的心脏肥大、纤维化和肾损伤。
DOI：
10.1089/10430340050129440
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Chao,J
中科院分区：
文献类型：
--
作者：
Zhang,JJ;Yoshida,H;Chao,L;Chao,J
肾上腺髓质素（AM）是一种强有力的血管扩张剂，在心、肾功能相关组织中表达。我们以前的研究表明，以裸DNA形式递送人类AM基因引起了长时间的 降低遗传性高血压大鼠的血压在这项研究中，我们评估了腺病毒介导的AM基因递送对高血压患者盐诱导的心肾损害的潜在保护作用。 Dahl盐敏感（DSS）大鼠。通过重组大肠杆菌，获得了携带巨细胞病毒启动子-增强子调控的人AM cDNA的腺病毒（Ad.CMV-hAM）。将重组人AM基因转染人胚肾293细胞，用放射免疫分析法检测其在细胞培养上清中的表达。单次静脉注射Ad.CMV-hAM引起了一系列的免疫反应。 与注射或不注射携带绿色荧光蛋白基因的腺病毒的对照大鼠相比，DSS大鼠的收缩压显著降低4周。AM基因递送 显著降低左心室质量和尿蛋白，增加cAMP水平，增强肾功能，如肾小球滤过率和肾血流量增加所证明。形态 研究表明，AM基因转移减少了心肌细胞直径和心脏间质纤维化，以及肾小球硬化，肾小管破坏和蛋白管型积聚。 肾在大鼠心脏、肾脏、肺、肝脏和主动脉中鉴定了人AM mRNA的表达，并测量了大鼠血浆和尿液中免疫反应性人AM水平。这些结果表明，人类 AM基因递送通过激活cAMP作为第二信使保护DSS大鼠免受盐诱导的高血压和心肾损伤。这些发现为AM的作用提供了新的见解 在盐引起的高血压，并可能在盐相关的心血管和肾脏疾病的治疗应用的影响。
Adrenomedullin (AM) is a potent vasodilator expressed in tissues relevant to cardiac and renal functions. Our previous study showed that delivery of the human AM gene in the form of naked DNA caused a prolonged reduction of blood pressure in genetically hypertensive rats. In this study, we evaluated potential protective effects of adenovirus-mediated AM gene delivery on salt-induced cardiorenal lesions in hypertensive Dahl saltsensitive (DSS) rats. Adenovirus carrying the human AM cDNA under the control of the cytomegalovirus promoter-enhancer (Ad.CMV-hAM) was generated by homologous recombination ofE. coli.Expression of recombinant human AM was detected by a radioimmunoassay in the medium of human embryonic kidney 293 cells transfected with Ad.CMV-hAM. A single intravenous injection of Ad.CMV-hAM caused a significant reduction of systolic blood pressure for 4 weeks in DSS rats compared with control rats with or without injection of adenovirus carrying the green fluorescent protein gene. AM gene delivery significantly reduced left ventricular mass and urinary protein, increased cAMP levels, and enhanced renal function as evidenced by increases in glomerular filtration rate and renal blood flow. Morphological investigations showed that AM gene transfer reduced cardiomyocyte diameter and interstitial fibrosis in the heart as well as glomerular sclerosis, tubular disruption, and protein cast accumulation in the kidney. Expression of human AM mRNA was identified in rat heart, kidney, lung, liver, and aorta, and immunoreactive human AM levels were measured in rat plasma and urine. These results indicate that human AM gene delivery protects against salt-induced hypertension and cardiac and renal lesions in DSS rats via activation of cAMP as a second messenger. These findings provide new insights into the role of AM in salt-induced hypertension and may have implications in therapeutic applications to salt-related cardiovascular and renal diseases.