Fritsch Samuel, Lindner Veronique, Welsch Sandra, Massfelder Thierry, Grima Michele, Rothhut Sylvie, Barthelmebs Mariette, Helwig Jean-Jacques
Renovascular Pharmacology and Physiology (INSERM), University of Louis Pasteur School of Medicine, Strasbourg, France.
J Am Soc Nephrol. 2004 Oct;15(10):2588-600. doi: 10.1097/01.ASN.0000141040.77536.AF.
While parathyroid hormone type 1 receptor (PTH1R)-mediated vasodilatory, cardiac stimulatory, and renin-activating effects of exogenous PTH/PTH-related protein (PTHrP) are acknowledged, interactions of endogenous PTHrP with these systems remain unclear, mainly because the unavailability of viable PTHrP/PTH1R knockout mice. Transgenic mice overexpressing PTH1R in smooth muscle strongly have supported the PTHrP/PTH1R system as a cardiovascular system (CVS) regulator, but the consequences on renovascular (RVS) and renin-angiotensin systems (RAS) have not been explored in these studies. The aim was to develop a model in which one could study the consequences on CVS, RVS, and RAS of generalized PTH1R overexpression. Systemic PTH1R cDNA plasmid delivery was used in adult rats, a system that is amenable to studies in isolated perfused kidneys and that minimizes development-induced compensatory mechanisms. Intravenous administration of hPTH1R or green fluorescence protein-tagged hPTH1R in pcDNA3 resulted 3 wk later, in generalized expression of hPTH1R (mRNA and protein), especially in vessels, liver, heart, kidney, and central nervous system, where it is expressed physiologically. As expected, PTH1R overexpression decreased BP and renal tone. Unexpected, however, PTH1R overexpression decreased heart rate. These studies also revealed that endogenous PTHrP actually inhibits renin release and that hPTH1R overexpression tends to increase that effect. Striking, liver production and circulatory level of angiotensinogen and hence plasma renin activity were markedly reduced. Thus, abrupt PTH1R overexpression in adult rats profoundly alters the CVS, RVS, and RAS, strongly supporting the PTH/PTHrP/PTH1R system as crucial for heart and vascular tone regulation. In addition, these results revealed that PTH1R-mediated mechanisms might have protective effects against cardiovascular stress-induced responses, including stimulations in heart rate and RAS.
虽然外源性甲状旁腺激素/甲状旁腺激素相关蛋白（PTHrP）通过1型甲状旁腺激素受体（PTH1R）介导的血管舒张、心脏刺激和肾素激活作用已得到公认，但内源性PTHrP与这些系统的相互作用仍不清楚，主要原因是缺乏可行的PTHrP/PTH1R基因敲除小鼠。在平滑肌中过度表达PTH1R的转基因小鼠有力地支持了PTHrP/PTH1R系统作为心血管系统（CVS）调节因子的作用，但这些研究尚未探讨其对肾血管系统（RVS）和肾素-血管紧张素系统（RAS）的影响。本研究的目的是建立一个模型，用于研究全身PTH1R过度表达对CVS、RVS和RAS的影响。将PTH1R cDNA质粒通过静脉注射给予成年大鼠，该系统适用于离体灌注肾研究，并能最大限度地减少发育诱导的代偿机制。3周后，静脉注射hPTH1R或pcDNA3中绿色荧光蛋白标记的hPTH1R，导致hPTH1R（mRNA和蛋白质）广泛表达，尤其是在血管、肝脏、心脏、肾脏和中枢神经系统中，这些组织在生理状态下也表达该蛋白。正如预期的那样，PTH1R过度表达降低了血压和肾张力。然而，出乎意料的是，PTH1R过度表达降低了心率。这些研究还表明，内源性PTHrP实际上抑制肾素释放，而hPTH1R过度表达倾向于增强这种作用。令人惊讶的是，肝脏中血管紧张素原的产生和循环水平以及血浆肾素活性均显著降低。因此，成年大鼠中PTH1R的突然过度表达深刻改变了CVS、RVS和RAS，有力地支持了PTH/PTHrP/PTH1R系统对心脏和血管张力调节至关重要。此外，这些结果表明，PTH1R介导的机制可能对心血管应激诱导的反应具有保护作用，包括心率和RAS的刺激。
