Dehmel B, Mervaala E, Lippoldt A, Gross V, Bohlender J, Ganten D, Luft F C
Franz Volhard Clinic, Medizinische Fakultät der Charité, Humboldt University of Berlin, Germany.
J Am Soc Nephrol. 1998 Dec;9(12):2212-22. doi: 10.1681/ASN.V9122212.
The hypertensive double transgenic rat harboring both the human renin and human angiotensinogen genes (dTGR) offers a unique opportunity to study the human renin-angiotensin system in an experimental animal model. Since nothing is known about the control of sodium and water excretion in these rats, this study was performed to compare pressure-natriuresis relationships in hypertensive dTGR and normotensive control rats harboring only the human renin gene (hREN), in order to determine how the pressure-natriuresis relationship is reset in hypertensive dTGR. To differentiate between extrinsic and intrinsic renal mechanisms, experiments were performed with and without renal denervation, and with and without infusions of vasopressin, norepinephrine, 17-OH-corticosterone, and aldosterone. Human and rat angiotensinogen and renin mRNA expression were also determined. In hREN without controlled renal function, urine flow and sodium excretion increased from 13 to 169 microl/min per g kidney wet weight (kwt) and from 1 to 30 micromol/min per g kwt, respectively, as renal perfusion pressure was increased from 67 to 135 mmHg. Renal blood flow (RBF) and GFR ranged between 3 to 7 and 0.9 to 1.5 ml/min per g kwt. In dTGR, pressure-natriuresis-diuresis relationships were shifted approximately 40 mmHg rightward. RBF was lower in dTGR than in hREN; GFR was not different. In dTGR with neurohormonal factors controlled, RBF was decreased and pressure-natriuresis-diuresis curves were not different compared to dTGR curves without these interventions. By light microscopy, the kidneys of these 6-wk-old dTGR and hREN rats were normal and indistinguishable. Both human and rat renin and angiotensinogen mRNA were expressed in the kidneys of dTGR. The two renin mRNA were decreased in dTGR, indicating a physiologic downregulation of renin gene expression by high BP. It is concluded that the renal pressure-natriuresis mechanism is reset toward higher pressure levels in dTGR and participates in the maintenance of hypertension. The reduced excretory function in dTGR depends on hREN and human angiotensinogen gene expression and is intrinsic to the kidney as opposed to extrarenal regulators.
携带人类肾素和人类血管紧张素原基因的高血压双转基因大鼠（dTGR）为在实验动物模型中研究人类肾素 - 血管紧张素系统提供了独特的机会。由于对这些大鼠的钠和水排泄控制情况一无所知，本研究旨在比较高血压dTGR和仅携带人类肾素基因的正常血压对照大鼠（hREN）的压力 - 利钠关系，以确定高血压dTGR中压力 - 利钠关系是如何重新设定的。为了区分外在和内在的肾脏机制，在有和没有肾去神经支配以及有和没有输注血管加压素、去甲肾上腺素、17 - 羟基皮质酮和醛固酮的情况下进行了实验。还测定了人类和大鼠血管紧张素原及肾素mRNA的表达。在肾功能未受控制的hREN中，随着肾灌注压从67 mmHg升高到135 mmHg，尿流率和钠排泄量分别从每克肾湿重（kwt）13微升/分钟增加到169微升/分钟，以及从每克kwt 1微摩尔/分钟增加到30微摩尔/分钟。肾血流量（RBF）和肾小球滤过率（GFR）范围分别为每克kwt 3至7毫升/分钟和0.9至1.5毫升/分钟。在dTGR中，压力 - 利钠 - 利尿关系向右移位约40 mmHg。dTGR中的RBF低于hREN；GFR无差异。在神经激素因素得到控制的dTGR中，RBF降低，与未进行这些干预的dTGR曲线相比，压力 -利钠 - 利尿曲线无差异。通过光学显微镜观察，这些6周龄的dTGR和hREN大鼠的肾脏正常且难以区分。dTGR的肾脏中同时表达了人类和大鼠的肾素及血管紧张素原mRNA。dTGR中两种肾素mRNA均减少，表明高血压对肾素基因表达有生理性下调作用。结论是，dTGR的肾脏压力 - 利钠机制向更高压力水平重新设定，并参与高血压的维持。dTGR中排泄功能的降低依赖于hREN和人类血管紧张素原基因的表达，且是肾脏内在的，而非肾外调节因素所致。
