Autoregulatory Impairment in Salt-Sensitive Hypertension

目前的建议将确定P2受体在盐敏感性高血压动物的传入小动脉表现出的受损的自我调节行为中的作用。重点将集中在微血管P2受体刺激ATP的反应。我们实验室以前的工作已经暗示ATP作为盐敏感致密斑细胞释放的信使分子，影响肾小球前阻力的自动调节。ATP也被认为是肾脏对盐增加的反应中的基本元素。初步数据表明，自身调节能力和对P2受体的反应性， 在血管紧张素II输注的高血压大鼠的肾脏中的传入小动脉中，ATP的激活减弱。这些观察结果支持了中心假设，即P2受体介导传入小动脉直径的自动调节，并且P2受体活化在高血压中通过局部产生的细胞因子的作用受损。因此，实验将集中于高血压和血压正常大鼠的传入小动脉对P2受体刺激的区域反应性，并将评估特定肾细胞因子对这些反应的影响。具体目标#1将检验P2降低的假设 受体活化介导盐敏感性高血压动物肾脏中的自动调节反应的损伤具体目标#2将检验局部产生的细胞因子损害传入小动脉反应性P2受体激活的假设。这些研究将集中在微血管对P2受体激活的反应性和它们在传入小动脉的肌源性和TGF依赖性区域中利用的钙内流途径。具体目标#3将检验这一假设，即流入依赖性Ca 2+信号传导机制是动物自身调节反应受损的原因 出现盐敏感性高血压我们将使用来自正常和高盐饮食的血压正常和高血压大鼠肾脏的新鲜分离的肾小球前平滑肌细胞。将使用fura-2检查P2受体激活引起的钙信号传导途径。我们将评估长期输注IL-6或TGF-β对P2受体刺激引起的钙内流途径的影响。

The current proposal will determine the role of P2 receptors in the impaired autoregulatory behavior exhibited by afferent arterioles from salt-sensitive hypertensive animals. Emphasis will focus on the responsiveness of the microvasculature to P2 receptor stimulation by ATP. Previous work from our laboratory has implicated ATP as the messenger molecule released from salt-sensing, macula densa cells to effect autoregulatory adjustments in preglomerular resistance. ATP is also considered to be essential element in the renal response to increased salt. Preliminary data indicate that autoregulatory capability and responsiveness to P2 receptor activation by ATP is attenuated in afferent arterioles in kidneys from angiotensin II-infused hypertensive rats. These observations support the central hypothesis that P2 receptors mediate autoregulatory adjustments in afferent arteriolar diameter and that P2 receptor activation is impaired in hypertension by the actions of locally generated cytokines. Accordingly, experiments will focus on the regional responsiveness of afferent arterioles from hypertensive and normotensive rats, to P2 receptor stimulation and will assess the impact of specific renal cytokines on these responses. Specific Aim #1 will test the hypothesis that decreased P2 receptor activation mediates impairment of autoregulatory responses in kidneys from salt-sensitive hypertensive animals.. Specific Aim #2 will test the hypothesis that locally generated cytokines impair afferent arteriolar responsiveness P2 receptor activation. These studies will focus on the microvascular responsiveness to P2 receptor activation and the calcium influx pathways utilized by them in the myogenic and TGF-dependent regions of the afferent arteriole. Specific Aim #3 will test the hypothesis that influx-dependent Ca 2+ signaling mechanisms are responsible for impaired autoregulatory responsiveness in animals developing salt-sensitive hypertension. We will use freshly isolated preglomerular smooth muscle cells from kidneys of normotensive and hypertensive rats fed normal and high salt diets. Calcium signaling pathways invoked by P2 receptor activation will be examined using fura-2. We will assess the impact of chronic infusions of IL-6 or TGF-beta on the calcium influx pathways invoked by P2 receptor stimulation.