Purinergic Regulation of the Renal Microcirculation

肾脏微循环的嘌呤能调节

• 批准号: 7786252
• 负责人: Edward W Inscho
• 金额: $ 30.93万
• 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/7786252
• 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）：自动调节是肾小球前微血管系统的固有特性，在血管紧张素II高血压6天内开始失效，导致动脉压向肾小球的传递增加。肾小球毛细血管压力慢性升高是高血压肾损害的主要危险因素。在Ang II高血压患者中，压力介导的自身调节性血管收缩功能下降的机制尚不清楚。P2 X1受体在介导传入小动脉自身调节行为中至关重要。P2 X1受体失活损害自身调节反应。Ang II高血压使自动调节减弱50%，并损害P2 X1受体介导的血管收缩和Ca 2+信号传导反应。血管紧张素II高血压和P2 Y12受体激活，有助于炎症和纤维化，并汇聚在自动调节效率的损失。氯吡格雷选择性阻断ADP敏感性P2 Y12受体，减少肾纤维化而不降低血压。氯吡格雷还可抑制MCP-1、TGF-β纤连蛋白和派-1，所有这些都与肾损伤有关。因此，该竞争性更新申请将解决中心假设，即涉及P2 Y12受体激活的炎症过程有助于P2 X1受体介导的传入小动脉血管收缩受损，肾脏自动调节控制受损，并导致Ang-II依赖性高血压的肾损伤。研究将确定P2 Y12受体阻滞剂对Ang-II型高血压中受损的自动调节、对P2受体刺激的传入小动脉反应性和肾内炎症介质激活的影响。具体目标1将检验P2 Y12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的假设。具体目标2将检验以下假设：P2 Y12受体依赖性机制导致传入小动脉对P2受体激活的反应受损，从而导致传入小动脉自动调节行为受损。具体目标3将检验P2 Y12受体刺激损害肾微血管反应性的炎性介质的表达，导致自身调节功能障碍和肾损伤的假设。这些研究将为P2 Y12受体和炎症在P2受体介导的肾微血管功能调节中的作用、自身调节行为以及P2 X1受体激活与Ang-II高血压肾损伤的关系提供新的信息。 公共卫生相关性高血压肾损伤在西方文化中是一个日益严重的问题。大部分损伤与压力相关的肾血管功能损害有关。本申请将阐述高血压引起的肾血管功能损害的机制及其与高血压肾损害的关系。