Lemmer Björn, Witte Klaus, Enzminger Helene, Schiffer Sabine, Hauptfleisch Stefan
Institute of Pharmacology and Toxicology, Ruprecht-Karls-University of Heidelberg, Mannheim, Germany.
Chronobiol Int. 2003 Jul;20(4):711-38. doi: 10.1081/cbi-120022407.
In transgenic hypertensive TGR(mREN2)27 rats (TGR) harboring the murine Ren-2 gene an inverse 24h blood pressure (BP) profile was described in relation to a normal pattern in heart rate (HR) and motility (MA), normotensive Sprague-Dawley rats (SDR) were used as controls. Transgenic rats as an animal model of human secondary hypertension (non-dipper) was studied in detail at different levels: (1) Radiotelemetry was applied to document gross circadian rhythms/rhythm disturbances in cardiovascular functions, MA and body temperature under normal LD conditions, under DD and after a light pulse. (2) Signal transduction of the overexpressed renin-angiotensin in TGR was studied by determation of AT1-receptors in kidney glomeruli together with kidney functions. (3) Expression of key processes involved in increased sympathetic regulation in TGR, mRNAs, the tyrosine-hydroxylase (TH) and norepinephrine (NE) reuptake1-carrier were determined. (4) In the SCN mRNA of c-fos and c-jun were determined under LD and after light pulse. (5) In primary cultures of pinealocytes the effects of adrenergic agonists and antagonists were evaluated on second messenger (cAMP, cGMP) accumulation and melatonin release. The results of these studies clearly demonstrate that the additional mouse renin genin in TGR greatly affected not only the renin-angiotensin-system and led--as expected--to an increased BP in this rat but also disturbed circadian rhythms from the BP pattern down to the level of hormones, processes of signal transduction, and expression of transcription factors and clock genes. In conclusion, the expression of a single additional gene is able to disturb the circadian system of an animal in a highly complex way. These findings are importance for chronobiologic as well as pharmacologic research.
在携带鼠Ren-2基因的转基因高血压TGR（mREN2）27大鼠（TGR）中，描述了与正常心率（HR）和运动性（MA）模式相关的24小时血压（BP）反向模式，正常血压的Sprague-Dawley大鼠（SDR）用作对照。转基因大鼠作为人类继发性高血压（非勺型）的动物模型，在不同层面进行了详细研究：（1）应用无线电遥测技术记录正常光照-黑暗（LD）条件下、持续黑暗（DD）条件下以及光脉冲后心血管功能、MA和体温的总体昼夜节律/节律紊乱情况。（2）通过测定肾小球中的AT1受体以及肾功能，研究TGR中过表达的肾素-血管紧张素的信号转导。（3）测定TGR中参与交感神经调节增加的关键过程的mRNA、酪氨酸羟化酶（TH）和去甲肾上腺素（NE）再摄取1载体的表达。（4）在LD条件下和光脉冲后，测定视交叉上核（SCN）中c-fos和c-jun的mRNA。（5）在松果体细胞原代培养物中，评估肾上腺素能激动剂和拮抗剂对第二信使（cAMP、cGMP）积累和褪黑素释放的影响。这些研究结果清楚地表明，TGR中额外的小鼠肾素基因不仅极大地影响了肾素-血管紧张素系统，并如预期导致该大鼠血压升高，还扰乱了从血压模式到激素水平、信号转导过程以及转录因子和生物钟基因表达的昼夜节律。总之，单个额外基因的表达能够以高度复杂的方式扰乱动物的昼夜节律系统。这些发现对时间生物学以及药理学研究具有重要意义。
