Bachmann S, Peters J, Engler E, Ganten D, Mullins J
Department of Anatomy of Heidelberg, Germany.
Kidney Int. 1992 Jan;41(1):24-36. doi: 10.1038/ki.1992.4.
Transgenic rats [TGR; strain name TGR(mRen2)27] harboring the mouse Ren-2 renin gene have been recently generated as a model for the study of primary hypertension that offers the advantage of a clearly-defined genetic alteration. Expression of the mouse Ren-2 gene causes severe hypertension (200 to 260 mm Hg) which is responsive to converting enzyme inhibitors. Compared to control transgene-negative littermates, plasma renin and angiotensin II values are lowered in TGR, whereas plasma prorenin values are strongly elevated. The adrenal gland in TGR shows marked overexpression of mouse renin messenger RNA; in situ hybridization using a 35S-labelled mouse-renin RNA probe reveals that enhanced renin expression is mainly localized to cells of the zona glomerulosa and outer zona fasciculata. Immunohistochemically, renin protein in the TGR adrenal gland is stored in larger quantities than in controls. Adrenal transgene expression probably accounts for most of the elevated plasma prorenin level in TGR, since bilateral adrenalectomy (ADX) causes a significant decrease in prorenin level (318 +/- 79 ng angiotensin I/ml/hr before ADX to 70 +/- 43 ng 4 days after ADX, P less than 0.0005). In the kidney, renin synthesis is almost completely suppressed in TGR. In situ hybridization demonstrates that few juxtaglomerular afferent arterioles express renin. Immunohistochemically, the TGR kidney shows significantly reduced renin and angiotensin II immunoreactivity at the afferent arteriole. Ultrastructural analysis of the afferent arteriolar wall frequently shows the complete absence of renin secretory granules since the granular cells are mostly converted into smooth muscle cells. Beginning at an age of approximately four to six months, TGR develop hypertension-related alterations and pathological lesions in various tissues. In the kidney, the wall thickness of arterioles and arteries is strongly increased, and glomerular lesions including different stages of sclerosis are observed. The thoracic aorta displays a considerable increase in tunica media thickness due to both myocyte hypertrophy and interstitial fibrosis. Coronary arteries and arterioles of the heart are thickened and perivascular fibrosis is observed. The data show that TGR(mRen2)27 transgenic rats display all typical characteristics of hypertensive pathology, making them an interesting model for therapeutic interventions. The fact that these changes occur in animals with a single gene difference to normotensive rats makes them a particularly suitable model for studies on gene-related hypertensive processes.
携带小鼠Ren-2肾素基因的转基因大鼠[TGR；品系名称TGR(mRen2)27]最近被培育出来，作为研究原发性高血压的模型，该模型具有明确界定的基因改变这一优势。小鼠Ren-2基因的表达会导致严重高血压（200至260毫米汞柱），且对转化酶抑制剂有反应。与对照转基因阴性同窝仔鼠相比，TGR的血浆肾素和血管紧张素II值降低，而血浆前肾素值则大幅升高。TGR的肾上腺显示小鼠肾素信使RNA明显过表达；使用35S标记的小鼠肾素RNA探针进行原位杂交显示，肾素表达增强主要定位于球状带和束状带外层的细胞。免疫组织化学分析表明，TGR肾上腺中的肾素蛋白储存量比对照多。肾上腺转基因表达可能是TGR血浆前肾素水平升高的主要原因，因为双侧肾上腺切除术（ADX）会导致前肾素水平显著下降（ADX前为318±79纳克血管紧张素I/毫升/小时，ADX后4天为70±43纳克，P<0.0005）。在肾脏中，TGR的肾素合成几乎完全受到抑制。原位杂交表明，很少有肾小球旁传入小动脉表达肾素。免疫组织化学分析显示，TGR肾脏的传入小动脉处肾素和血管紧张素II免疫反应性显著降低。对传入小动脉壁的超微结构分析经常显示完全没有肾素分泌颗粒，因为颗粒细胞大多已转化为平滑肌细胞。从大约四到六个月龄开始，TGR在各种组织中出现与高血压相关的改变和病理病变。在肾脏中，小动脉和动脉的壁厚度显著增加，并观察到包括不同硬化阶段的肾小球病变。胸主动脉由于心肌细胞肥大和间质纤维化，中膜厚度显著增加。心脏的冠状动脉和小动脉增厚，并观察到血管周围纤维化。数据表明，TGR(mRen2)27转基因大鼠表现出高血压病理学的所有典型特征，使其成为治疗干预研究的一个有趣模型。这些变化发生在与正常血压大鼠只有一个基因差异的动物身上，这一事实使其成为研究基因相关高血压过程的特别合适的模型。
