Murakami H, Yayama K, Chao L, Chao J
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, USA.
Kidney Int. 1998 May;53(5):1305-13. doi: 10.1046/j.1523-1755.1998.00867.x.
The tissue kallikrein-kinin system has been shown to play important roles in cardiovascular and renal function. The aim of this study was to investigate potential protective effects of kallikrein gene delivery in gentamycin-induced nephrotoxicity. Rats were injected subcutaneously with gentamycin daily for 10 to 14 days. Adenovirus, Ad.CMV-cHK carrying the human tissue kallikrein gene or Ad.CMV-LacZ carrying the beta-galactosidase gene under the control of the cytomegalovirus promoter, were delivered intravenously on the first day of gentamycin administration. The expression of human tissue kallikrein mRNA was identified in the kidney, aorta, heart and liver and immunoreactive human kallikrein levels were measured in the serum and urine of rats receiving kallikrein gene delivery. Adenovirus-mediated kallikrein gene delivery significantly increased the renal blood flow, glomerular filtration rates, and urine flow while it attenuated renal tubular damage, cellular necrosis, lumenal protein casts and reduced ventricular weight and cardiomyocyte size. Kallikrein gene delivery caused a decrease in blood urea nitrogen levels and increases in urinary kinin and nitrite/nitrate levels. This study shows that kallikrein gene delivery exhibits protection against gentamycin-induced nephrotoxicity, and raises the potential for kallikrein gene therapy to treat drug-induced renal diseases.
组织激肽释放酶-激肽系统已被证明在心血管和肾功能中发挥重要作用。本研究的目的是探讨激肽释放酶基因递送对庆大霉素诱导的肾毒性的潜在保护作用。大鼠每天皮下注射庆大霉素，持续10至14天。在庆大霉素给药的第一天，静脉注射携带人组织激肽释放酶基因的腺病毒Ad.CMV-cHK或携带在巨细胞病毒启动子控制下的β-半乳糖苷酶基因的腺病毒Ad.CMV-LacZ。在肾脏、主动脉、心脏和肝脏中鉴定出人组织激肽释放酶mRNA的表达，并在接受激肽释放酶基因递送的大鼠的血清和尿液中测量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显著增加肾血流量、肾小球滤过率和尿量，同时减轻肾小管损伤、细胞坏死、管腔内蛋白管型，并减轻心室重量和心肌细胞大小。激肽释放酶基因递送导致血尿素氮水平降低，尿激肽和亚硝酸盐/硝酸盐水平升高。本研究表明，激肽释放酶基因递送对庆大霉素诱导的肾毒性具有保护作用，并提高了激肽释放酶基因治疗药物性肾病的潜力。
