Noonan William T, Qian Jin, Stuart William D, Clemens Thomas L, Lorenz John N
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, Ohio 45267-0576.
Endocrinology. 2003 Nov;144(11):4931-8. doi: 10.1210/en.2003-0351. Epub 2003 Jul 17.
PTH-related protein (PTHrP) is an autocrine/paracrine peptide expressed in renal tubules and vasculature and may play an important role in regulating overall renal function. To evaluate the potential role of endogenous PTHrP in the control of renal hemodynamics, we performed clearance measurements in transgenic (TG) mice in which the SMP8 alpha-actin promoter was used to drive overexpression of the PTH/PTHrP type 1 receptor in smooth muscle. In protocol I, responses to acute saline volume expansion (SVE, 0.75 microl/min.g body weight) were measured in TG and nontransgenic (NTG) mice. Mean arterial pressure was significantly lower in TG mice throughout the experiment, and it decreased comparably in both groups in response to SVE. SVE significantly increased effective renal plasma flow in both groups of mice, but the increase was greater in TG than in NTG. Glomerular filtration rate decreased in response to SVE in NTG but did not change in TG animals. In protocol II, renal responses to angiotensin II (ANG II) infusion were determined (0.5 ng/min.g body weight). Baseline arterial pressure was again significantly lower in TG, compared with NTG mice, and TG mice had a blunted pressor response to ANG II. Also, ANG II decreased effective renal plasma flow and glomerular filtration rate in both groups of animals, but the reductions were less in TG than in NTG mice. Our findings indicate that smooth-muscle-specific overexpression of the PTH/PTHrP type 1 receptor resulted in augmentation of the vasodilatory response to SVE and attenuation of the vasoconstrictor response to ANG II. We conclude that endogenous PTHrP can act as an endogenous vasorelaxant factor to modulate renal responses to vasoactive stimuli.
甲状旁腺激素相关蛋白（PTHrP）是一种在肾小管和血管中表达的自分泌/旁分泌肽，可能在调节整体肾功能中发挥重要作用。为了评估内源性PTHrP在控制肾血流动力学中的潜在作用，我们在转基因（TG）小鼠中进行了清除率测量，其中使用SMP8α-肌动蛋白启动子驱动平滑肌中甲状旁腺激素/甲状旁腺激素相关蛋白1型受体的过表达。在方案I中，测量了TG和非转基因（NTG）小鼠对急性生理盐水容量扩张（SVE，0.75微升/分钟·克体重）的反应。在整个实验过程中，TG小鼠的平均动脉压显著低于NTG小鼠，并且两组对SVE的反应均相应降低。SVE显著增加了两组小鼠的有效肾血浆流量，但TG组的增加幅度大于NTG组。NTG小鼠的肾小球滤过率在SVE时降低，但TG动物中未发生变化。在方案II中，确定了对血管紧张素II（ANG II）输注（0.5纳克/分钟·克体重）的肾反应。与NTG小鼠相比，TG小鼠的基线动脉压再次显著降低，并且TG小鼠对ANG II的升压反应减弱。此外，ANG II降低了两组动物的有效肾血浆流量和肾小球滤过率，但TG组的降低幅度小于NTG小鼠。我们的研究结果表明，平滑肌特异性过表达甲状旁腺激素/甲状旁腺激素相关蛋白1型受体导致对SVE的血管舒张反应增强以及对ANG II的血管收缩反应减弱。我们得出结论，内源性PTHrP可作为内源性血管舒张因子来调节肾脏对血管活性刺激的反应。
