Ganten D, Wagner J, Zeh K, Bader M, Michel J B, Paul M, Zimmermann F, Ruf P, Hilgenfeldt U, Ganten U
German Institute for High Blood Pressure Research, University of Heidelberg.
Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7806-10. doi: 10.1073/pnas.89.16.7806.
The renin-angiotensin system (RAS) is the most important regulatory system of electrolyte homeostasis and blood pressure. We report here the development of transgenic rats carrying the human angiotensinogen TGR-(hAOGEN) and human renin TGR(hREN) genes. The plasma levels and tissue distribution of the transcription and translation products from both genes are described. A unique species specificity of the enzyme kinetics was observed. The human RAS components in the transgenic rats did not interact with the endogenous rat RAS in vivo. Instead, infusions of exogenous human RAS components specifically interacted with human transgene translation products. Thus, infusion of human renin in TGR(hAOGEN) led to an increase of angiotensin II and an elevation of blood pressure, which could not be antagonized by the human-specific renin enzyme inhibitor Ro 42-5892. Rat renin also elevated blood pressure and angiotensin II in TGR(hAOGEN); however, this effect was not antagonized by the human renin inhibitor. Compared to mice, rats offer the advantage of chronic instrumentation and repetitive, sophisticated, hemodynamic, and endocrinological investigations. Thus, transgenic rat models with human-specific enzyme kinetics permit primate-specific analyses in non-primate in vivo and in vitro experimental systems.
肾素-血管紧张素系统（RAS）是电解质稳态和血压最重要的调节系统。我们在此报告携带人血管紧张素原的转基因大鼠TGR-(hAOGEN)和人肾素转基因大鼠TGR(hREN)的培育情况。描述了这两个基因转录和翻译产物的血浆水平及组织分布。观察到酶动力学具有独特的物种特异性。转基因大鼠中的人RAS成分在体内不与内源性大鼠RAS相互作用。相反，外源性人RAS成分的输注特异性地与人转基因翻译产物相互作用。因此，在TGR(hAOGEN)中输注人肾素导致血管紧张素II增加和血压升高，而人特异性肾素酶抑制剂Ro 42-5892无法拮抗这种作用。大鼠肾素也使TGR(hAOGEN)的血压和血管紧张素II升高；然而，这种作用不能被人肾素抑制剂拮抗。与小鼠相比，大鼠具有可进行慢性植入以及重复、复杂的血流动力学和内分泌学研究的优势。因此，具有人特异性酶动力学的转基因大鼠模型允许在非灵长类体内和体外实验系统中进行灵长类特异性分析。
