Yayama K, Wang C, Chao L, Chao J
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425-2211, USA.
Hypertension. 1998 May;31(5):1104-10. doi: 10.1161/01.hyp.31.5.1104.
To demonstrate potential therapeutic effects of kallikrein gene delivery, we delivered adenovirus (Ad.CMV-cHK) carrying the human tissue kallikrein gene into two-kidney, one-clip Goldblatt hypertensive rats. A single intravenous injection of the recombinant adenovirus caused a delay of blood pressure increase that began 1 day after injection and continued for 24 days. A maximal blood pressure reduction was observed in rats receiving kallikrein gene delivery compared with control rats receiving Ad.CMV-LacZ (160+/-5 versus 186+/-7 mm Hg, n=6, P<.01). The expression of human tissue kallikrein mRNA was identified in the kidney, heart, aorta, and liver of rats receiving kallikrein gene delivery. Immunoreactive human kallikrein levels were measured in rat serum and urine in a time-dependent manner. Adenovirus-mediated kallikrein gene delivery caused a significant reduction in the left ventricular mass and cardiomyocyte size, as well as an increase in renal blood flow, urine flow, glomerular filtration rates, electrolyte output, and urine excretion. Enhanced renal responses were accompanied by significant increases in urinary kinin, nitrite/nitrate, and cyclic GMP levels. These findings show that the expression of human tissue kallikrein via gene delivery has protective effects against renovascular hypertension and cardiovascular and renal dysfunction.
为了证明激肽释放酶基因递送的潜在治疗效果，我们将携带人组织激肽释放酶基因的腺病毒（Ad.CMV-cHK）导入双肾单夹Goldblatt高血压大鼠体内。单次静脉注射重组腺病毒导致血压升高延迟，该延迟在注射后1天开始并持续24天。与接受Ad.CMV-LacZ的对照大鼠相比，接受激肽释放酶基因递送的大鼠观察到最大血压降低（160±5对186±7 mmHg，n = 6，P<0.01）。在接受激肽释放酶基因递送的大鼠的肾脏、心脏、主动脉和肝脏中鉴定出人组织激肽释放酶mRNA的表达。以时间依赖性方式测量大鼠血清和尿液中的免疫反应性人激肽释放酶水平。腺病毒介导的激肽释放酶基因递送导致左心室质量和心肌细胞大小显著降低，以及肾血流量、尿流量、肾小球滤过率、电解质输出和尿排泄增加。增强的肾脏反应伴随着尿激肽、亚硝酸盐/硝酸盐和环鸟苷酸水平的显著增加。这些发现表明，通过基因递送表达人组织激肽释放酶对肾血管性高血压以及心血管和肾脏功能障碍具有保护作用。
