Autoregulatory Impairment in Na-Sensitive hypertension

目前的提议将确定P2受体在盐敏感型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系统对三磷酸腺苷刺激的P2受体的反应。我们实验室以前的工作表明，ATP是从盐敏感的致密斑细胞中释放出来的信使分子，在肾小球前阻力中实施自我调节调节。三磷酸腺苷也被认为是肾脏对盐分增加反应的基本元素。初步数据表明，自我调节能力和对P2受体的反应性 血管紧张素II注射的高血压大鼠肾脏的传入小动脉中，ATP的激活作用减弱。这些观察结果支持中心假设，即P2受体介导传入小动脉内径的自我调节调节，并且P2受体的激活在局部产生的细胞因子的作用下在高血压中受损。因此，实验将集中在高血压和正常血压大鼠的传入小动脉对P2受体刺激的局部反应性，并将评估特定的肾脏细胞因子对这些反应的影响。具体目标#1将检验降低P2的假设 受体激活介导盐敏感型高血压动物肾脏自身调节反应的损害。特殊目的#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受体激活的反应性以及它们在传入小动脉的肌源性和转化生长因子依赖性区域利用的钙内流途径。具体目标#3将检验这一假说，即依赖内流的钙信号机制是动物自我调节反应受损的原因 患上盐敏感型高血压。我们将使用新鲜分离的来自正常血压和高血压大鼠肾脏的肾小球前平滑肌细胞，这些大鼠喂食正常和高盐饮食。P2受体激活所激活的钙信号通路将使用Fura-2进行检测。我们将评估慢性输注IL-6或转化生长因子-β对刺激P2受体激活的钙内流通路的影响。

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.