Autoregulatory Impairment in Salt-Sensitive Hypertension

盐敏感性高血压的自身调节损伤

• 批准号: 7433777
• 负责人: Edward W Inscho
• 金额: $ 29.38万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7433777
• 关键词: Acute; Affect; Angiotensin II; Animals; Attenuated; Behavior; Calcium; Calcium Signaling; Caliber; Cells; Chronic; Data; Development; Diet; End stage renal failure; Exhibits; Exposure to; Feedback; Functional disorder; Fura-2; Glomerular Capillary; Hypertension; Impairment; Indium; Infusion procedures; Interleukin-6; Juxtamedullary Nephron; Kidney; Laboratories; Macula densa; Measures; Mediating; Pathway interactions; Perfusion; Play; Production; Purinoceptor; Rattus; Receptor Activation; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Site; Smooth Muscle Myocytes; Sodium Chloride; Stress; Techniques; Testing; Tissue Sample; Transforming Growth Factor beta; Vascular Smooth Muscle; Video Microscopy; Work; arteriole; cytokine; day; feeding; normotensive; pressure; programs; receptor; research study; response; salt sensitive; vasoconstriction

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.

目前的提案将确定 P2 受体在盐敏感高血压动物传入小动脉表现出的自身调节行为受损中的作用。重点将集中于微脉管系统对 ATP 刺激 P2 受体的反应。我们实验室之前的工作表明，ATP 作为盐敏感黄斑细胞释放的信使分子，可影响肾小球前阻力的自动调节。 ATP 也被认为是肾脏对盐分增加的反应中的必需元素。初步数据表明，自身调节能力和对 P2 受体的反应性 输注血管紧张素 II 的高血压大鼠肾脏传入小动脉中 ATP 的激活减弱。这些观察结果支持以下中心假设：P2 受体介导传入小动脉直径的自动调节调节，并且高血压中 P2 受体的激活因局部产生的细胞因子的作用而受损。因此，实验将重点关注高血压和正常血压大鼠的传入小动脉对 P2 受体刺激的区域反应，并将评估特定肾细胞因子对这些反应的影响。具体目标 #1 将检验减少 P2 的假设 受体激活介导盐敏感性高血压动物肾脏自动调节反应的损害。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。这些研究将重点关注微血管对 P2 受体激活的反应以及它们在传入小动脉的肌源性和 TGF 依赖性区域中利用的钙流入途径。具体目标 #3 将检验以下假设：内流依赖性 Ca 2+ 信号传导机制导致动物自身调节反应能力受损 发展为盐敏感性高血压。我们将使用从喂食正常和高盐饮食的正常血压和高血压大鼠的肾脏中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通路。我们将评估长期输注 IL-6 或 TGF-β 对 P2 受体刺激引起的钙流入途径的影响。