Tokita Y, Franco-Saenz R, Mulrow P J
Department of Medicine, Medical College of Ohio, Toledo, USA.
Am J Hypertens. 1995 Oct;8(10 Pt 1):1031-9. doi: 10.1016/0895-7061(95)00270-7.
The transgenic rat TGR(mRen-2)27 develops severe hypertension with high adrenal renin and low kidney renin. The mechanism of suppressed kidney renin in these animals is still unclear. We investigated the effect of the angiotensin converting enzyme (ACE) inhibitor, perindopril on the renin-angiotensin system in plasma and tissues (adrenal gland and kidney), and the effect of mouse renin antibody on plasma and tissue renin activity before and after perindopril administration. Perindopril lowered blood pressure in the TGR(mRen-2)27 rats from 254.5 +/- 7.4 mm Hg to 154 +/- 7.8 mm hg (n = 8, P < .0001), while blood pressure in the untreated TGR (mRen-2)27 rats increased from 253.7 +/- 8.1 to 276.1 +/- 14.3 mm Hg during the study period. Perindopril significantly suppressed plasma angiotensin II (Ang II) from 19.4 +/- 2.5 pg/mL to 2.6 +/- 0.4 pg/mL, P < .0001, while markedly increasing plasma renin concentration (PRC) from 15.5 +/- 1.8 ng AngI/mL/h to 148.2 +/- 35.5 ng AngI/mL/h, P < .005 and kidney renin from 56.7 +/- 18.1 micrograms AngI/g/h to 827.4 +/- 79.1 micrograms AngI/g/h, P < .0001. However, adrenal renin was not increased. A mouse Ren-2 renin antibody at a 1:1000 dilution that suppresses purified mouse Ren-2 renin activity by 62.6 +/- 3.6% (n = 3, P < .0001) and does not suppress renin activity in plasma and kidney of the Sprague-Dawley rats, suppressed PRC in the untreated TGR(mRen-2)27 rats by 52.3 +/- 3.5% (n = 6, P < .0001). However, it only suppressed PRC in the perindopril treated TGR(mRen-2)27 rats by 7.0 +/- 2.4% (n = 6, P < .05). The antibody suppressed adrenal renin in both untreated and perindopril treated TGR(mREN-2)27 rats by 57.3 +/- 5.4% (n = 5, P < .0001) and 49.7 +/- 2.2% (n = 6, P < .0001), respectively. On the other hand, the mouse antibody suppressed kidney renin in the untreated TGR(mRen-2)27 rats by only 11.0 +/- 3.3% (n = 6, P < .05), and did not suppress kidney renin in the perindopril treated TGR(mRen-2)27 rats (n = 6, P < .0001), respectively. On the other hand, the mouse antibody suppressed kidney renin in the untreated TGR(mRen-2)27 rats by only 11.0 +/- 3.3% (n = 6, P < .05), and did not suppress kidney renin in the perindopril treated TGR(mRen-2)27 rats (n = 6, P < NS). The pH profile of renin activity in plasma confirmed the results of the antibody study. We conclude that in the TGR(mRen-2)27 rats adrenal renin is mainly mouse renin and kidney renin is mainly rat renin. The main sources of circulating renin in the TGR(mRen-2)27 rats are extra-renal tissues, including the adrenal glands, where mouse Ren-2 renin transcripts are highly expressed. The increased circulating renin in perindopril treated TGR(mRen-2)27 rats is rat renin derived from the kidney. The failure of adrenal renin to increase with perindopril suggests that at least in the basal state there is no feedback inhibition as there is in the kidney. The low kidney renin appears to be due to physiological rather than genetic factors.
转基因大鼠TGR(mRen-2)27会出现严重高血压，伴有肾上腺肾素水平升高和肾脏肾素水平降低。这些动物肾脏肾素受抑制的机制仍不清楚。我们研究了血管紧张素转换酶（ACE）抑制剂培哚普利对血浆和组织（肾上腺和肾脏）肾素-血管紧张素系统的影响，以及在培哚普利给药前后小鼠肾素抗体对血浆和组织肾素活性的影响。培哚普利使TGR(mRen-2)27大鼠的血压从254.5±7.4 mmHg降至154±7.8 mmHg（n = 8，P <.0001），而在研究期间，未治疗的TGR(mRen-2)27大鼠的血压从253.7±8.1 mmHg升至276.1±14.3 mmHg。培哚普利显著抑制血浆血管紧张素II（Ang II），从19.4±2.5 pg/mL降至2.6±0.4 pg/mL，P <.0001，同时显著增加血浆肾素浓度（PRC），从15.5±1.8 ng AngI/mL/h升至148.2±35.5 ng AngI/mL/h，P <.005，肾脏肾素从56.7±18.1 μg AngI/g/h升至827.4±79.1 μg AngI/g/h，P <.0001。然而，肾上腺肾素并未增加。一种1:1000稀释的小鼠Ren-2肾素抗体可使纯化的小鼠Ren-2肾素活性抑制62.6±3.6%（n = 3，P <.0001），且不抑制Sprague-Dawley大鼠血浆和肾脏中的肾素活性，该抗体使未治疗的TGR(mRen-2)27大鼠的PRC抑制52.3±3.5%（n = 6，P <.0001）。然而，它仅使培哚普利治疗的TGR(mRen-2)27大鼠的PRC抑制7.0±2.4%（n = 6，P <.05）。该抗体在未治疗和培哚普利治疗的TGR(mREN-2)27大鼠中分别使肾上腺肾素抑制57.3±5.4%（n = 5，P <.0001）和49.7±2.2%（n = 6，P <.0001）。另一方面，该小鼠抗体在未治疗的TGR(mRen-2)27大鼠中仅使肾脏肾素抑制11.0±3.3%（n = 6，P <.05），在培哚普利治疗的TGR(mRen-2)27大鼠中未抑制肾脏肾素（n = 6，P < NS）。血浆中肾素活性的pH曲线证实了抗体研究的结果。我们得出结论，在TGR(mRen-2)27大鼠中，肾上腺肾素主要是小鼠肾素，肾脏肾素主要是大鼠肾素。TGR(mRen-2)27大鼠循环肾素 的主要来源是肾外组织，包括肾上腺，其中小鼠Ren-2肾素转录本高度表达。培哚普利治疗的TGR(mRen-2)27大鼠中循环肾素增加是来自肾脏的大鼠肾素。培哚普利治疗后肾上腺肾素未增加，这表明至少在基础状态下，不像在肾脏中那样存在反馈抑制。肾脏肾素水平低似乎是由于生理因素而非遗传因素。
