Purinergic Regulation of the Renal Microcirculation

肾脏微循环的嘌呤能调节

• 批准号: 7588007
• 负责人: Edward W Inscho
• 金额: $ 31.24万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588007
• 关键词: Address; Adenosine; Albumins; Behavior; Blood Pressure; Chronic; Evaluation; Excretory function; Fibronectins; Fibrosis; Functional disorder; Gelatinase B; Glomerular Capillary; Homeostasis; Hypertension; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Infusion procedures; Injury; Juxtamedullary Nephron; Kidney; Lead; Link; Measures; Mediating; Microcirculation; Monocyte Chemoattractant Protein-1; Plasminogen Activator Inhibitor 1; Plasminogen Inactivators; Platelet Activation; Process; Property; Rattus; Receptor Activation; Regulation; Research; Risk Factors; Role; Signal Transduction; Signaling Molecule; Stress; Testing; Time; Transforming Growth Factors; arteriole; clopidogrel; in vivo; kidney vascular structure; normotensive; pressure; programs; protective effect; public health relevance; receptor; research study; response; transmission process; urinary; vascular inflammation; vasoconstriction

DESCRIPTION (provided by applicant): Autoregulation is an intrinsic property of the preglomerular microvasculature that begins to fail within 6 days of Ang II hypertension resulting in increased transmission of arterial pressure to the glomerulus. Chronic elevation of glomerular capillary pressure is a major risk factor for hypertensive renal injury. The mechanisms responsible for the decline in pressure-mediated autoregulatory vasoconstriction in Ang II hypertension remain unclear. P2X1 receptors are critically important in mediating afferent arteriolar autoregulatory behavior. P2X1 receptor inactivation impairs autoregulatory responses. Ang II hypertension blunts autoregulation by 50% and impairs P2X1 receptor-mediated vasoconstriction and Ca2+ signaling responses. Ang II hypertension, and P2Y12 receptor activation, contribute to inflammation and fibrosis and converge on a loss of autoregulatory efficiency. Clopidogrel selectively blocks ADP sensitive P2Y12 receptors and reduces renal fibrosis without decreasing blood pressure. Clopidogrel also inhibits expression of MCP-1, TGF-?, fibronectin, and PAI-1, all of which are associated with renal injury. Therefore, this competing renewal application will address the central hypothesis that inflammatory processes involving P2Y12 receptor activation contribute to impairment of P2X1 receptor-mediated afferent arteriolar vasoconstriction, impairment of renal autoregulatory control and leads to renal injury in Ang-II-dependent hypertension. Studies will establish the impact of P2Y12 receptor blockade on impaired autoregulation in Ang-II hypertension, afferent arteriolar responsiveness to P2 receptor stimulation and activation of intrarenal inflammatory mediators. Specific aim 1 will test the hypothesis that P2Y12 receptor-dependent inflammatory processes contribute to the decline in autoregulatory control observed in Ang II hypertension. Specific aim 2 will test the hypothesis that P2Y12 receptor-dependent mechanisms contribute to impairment of afferent arteriolar responses to P2 receptor activation resulting in impaired afferent arteriolar autoregulatory behavior. Specific aim 3 will test the hypothesis that P2Y12 receptors stimulate expression of inflammatory mediators that impair renal microvascular reactivity, leading to autoregulatory dysfunction and renal injury. These studies will provide new information on the role of P2Y12 receptors and inflammation on P2 receptor- mediated regulation of renal microvascular function, autoregulatory behavior and the relationship between P2X1 receptor activation and Ang-II hypertensive renal injury. PUBLIC HEALTH RELEVANCE Hypertensive renal injury is a growing problem in western cultures. Much of the injury relates to pressure- related impairment of renal vascular function. This application will address the mechanisms responsible for hypertension-induced impairment of renal vascular function and its relationship to hypertensive kidney damage.

描述（由申请人提供）：自动调节是骨膜前微脉管系统的内在特性，在ANG II高血压的6天内开始失败，导致动脉压增加向肾小球。肾小球毛细管压力的慢性升高是高血压肾脏损伤的主要危险因素。导致压力介导的自动调节性血管收缩下降的机制尚不清楚。 P2X1受体在介导传入小动脉自动调节行为中至关重要。 P2X1受体失活会损害自动调节反应。 ANG II高血压钝性调节50％，并损害P2X1受体介导的血管收缩和Ca2+信号反应。 ANG II高血压和P2Y12受体激活有助于炎症和纤维化，并融合自动调节效率的丧失。氯吡格雷选择性地阻断ADP敏感的P2Y12受体并减少肾纤维化而不会降低血压。氯吡格雷还抑制MCP-1，TGF-？，纤连蛋白和PAI-1的表达，所有这些表达与肾损伤有关。因此，这种相互竞争的更新应用将解决以下中心假设：涉及P2Y12受体激活的炎症过程有助于P2X1受体介导的传入动脉血管收缩，肾脏自动调节性控制损害，并导致肾脏损伤受到抗血管损伤。研究将建立P2Y12受体阻滞对ANG-II高血压，传入小动脉刺激的反应和激活肾内炎症介质的自动调节受损的影响。具体目标1将检验以下假设：P2Y12受体依赖性炎症过程有助于在ANG II高血压中观察到的自动调节控制下降。具体目标2将检验以下假设：P2Y12受体依赖性机制有助于损害传入小动脉对P2受体激活的反应，从而导致传入小动脉自动调节行为受损。特定目标3将检验以下假设：P2Y12受体刺激炎症介质的表达，这些炎症介质会损害肾脏微血管反应性，从而导致自动调节功能障碍和肾脏损伤。这些研究将提供有关P2Y12受体以及炎症在P2受体介导的肾脏微血管功能，自动调节行为以及P2X1受体激活与ANG-II高血压肾脏损伤之间的关系的新信息。 公共卫生相关性高血压肾脏受伤是西方文化中日益增长的问题。大部分损伤与肾血管功能的压力相关损伤有关。该应用将解决导致高血压引起的肾血管功能损伤及其与高血压肾脏损伤的关系的机制。