Autoregulatory Impairment in Na-Sensitive hypertension

钠敏感性高血压的自身调节损伤

• 批准号: 6853169
• 负责人: Edward W Inscho
• 金额: $ 18.18万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6853169
• 关键词: adenosine triphosphate; angiotensin /renin /aldosterone hypertension; arterioles; biological signal transduction; blood vessel disorder; calcium indicator; calcium ion; cytokine; fluorescence spectrometry; immunocytochemistry; interleukin 6; kidney function; laboratory mouse; microcirculation; neuroregulation; purinergic receptor; receptor sensitivity; somatic afferent nerve; spontaneous hypertensive rat; transforming growth factors; vascular smooth muscle; video microscopy; western blottings

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.

当前的建议将确定P2受体在盐敏感高血压动物中传入小动脉表现出的自动调节行为中的作用。重点将集中于微脉管系统对P2受体刺激的反应性。我们实验室的先前工作涉及ATP，因为从盐感应，黄斑densa细胞释放的信使分子以实现骨膜前耐药性的自动调节调整。 ATP也被认为是肾脏对增加盐的反应中的重要元素。初步数据表明自动调节能力和对P2受体的响应能力 来自血管紧张素II注入的高血压大鼠的肾脏传入小动脉中ATP激活。这些观察结果支持了一个中心假设：P2受体介导传入小动脉直径的自动调节调节，并且P2受体激活受到局部产生的细胞因子的作用而损害了高血压。因此，实验将集中于传入小动脉的区域反应性，从高血压和正常的大鼠到P2受体刺激，并评估特定肾细胞因子对这些反应的影响。特定目标＃1将检验降低P2的假设 受体激活介导了来自盐敏感性高血压动物的肾脏自动调节反应的损害。特定的目标＃2将检验以下假设：局部产生的细胞因子会损害传入的动脉反应性P2受体激活。这些研究将集中于对P2受体激活的微血管反应性以及它们在传入小动脉的肌源性和TGF依赖性区域中使用的钙涌入途径。具体目标＃3将检验以下假设：依赖涌入的Ca 2+信号传导机制导致动物自动调节反应性受损 发展盐敏感的高血压。我们将使用正常和高盐饮食的正常和高血压大鼠肾脏中新鲜分离的前平滑肌细胞。 P2受体激活引用的钙信号通路将使用Fura-2检查。我们将评估IL-6或TGF-β慢性输注对P2受体刺激引用的钙涌入途径的影响。