The Inflammatory Cytokines, MCP-1 and TGF-Beta, Mediate Renal Autoregulatory Impa

炎症细胞因子 MCP-1 和 TGF-Beta 介导肾脏自动调节影响

基本信息

批准号：
7753439
负责人：
Edward W Inscho
金额：
$ 36.75万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-04 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7753439
关键词：
Acute Address Anti-Inflammatory Agents Anti-inflammatory Attenuated Behavior CCL2 gene Calcium Signaling Chronic Data Development Event Exposure to Functional disorder Glomerular Capillary Homeostasis Hydrogen Peroxide Hypertension Impairment Inflammation Inflammation Mediators Inflammatory Injury Kidney Left Link Mediating Mediator of activation protein P2X-receptor Pentosan Polysulfate Play Process Production Property Rattus Reactive Oxygen Species Receptor Activation Receptor Signaling Renal function Research Risk Factors Role Signal Transduction Signaling Molecule Superoxides Testing Transforming Growth Factor beta Vascular Smooth Muscle Vasoconstrictor Agents Work adenosine receptor activation arteriole cytokine improved insight kidney vascular structure monocyte chemoattractant protein 1 receptor mycophenolate mofetil normotensive pressure prevent public health relevance receptor research study response transmission process vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Elevation of glomerular capillary pressure is a major risk factor for hypertensive renal injury. Ang II hypertension impairs autoregulation and eliminates P2X1 receptor- mediated vasoconstriction, which is critically important for mediating afferent arteriolar autoregulatory behavior. Impaired autoregulation in hypertension coincides with increased renal cytokine production, such as TGF-2 and MCP-1, which may be involved in hypertension-induced renal microvascular dysfunction. Project 2 will determine the role of these cytokines on afferent arteriolar dysfunction in Ang II infused hypertension. Preliminary data indicate that anti-inflammatory treatment prevents afferent arteriolar dysfunction in hypertension. TGF- 2 inhibits autoregulatory responses. Furthermore, MCP-1 inhibition with CCR2 receptor blockade improves autoregulatory efficiency in hypertensive kidneys. These data support the central hypothesis of Project 2 that hypertension initiates intrarenal inflammatory events that result in afferent arteriolar dysfunction and renal injury by impairing P2X1 receptor signaling. Ang II-infused hypertensive rats will be treated with the anti-inflammatory agents, pentosan polysulfate or mycophenolate mofetil, to inhibit inflammatory processes. Experiments will establish the impact of anti-inflammatory treatment on impaired arteriolar autoregulatory behavior, reduced afferent arteriolar reactivity to P2 receptor stimulation, preglomerular vascular smooth muscle Ca2+ signaling mechanisms and expression and function of ROS and intrarenal inflammatory mediators in hypertensive and normotensive rats. These objectives will be addressed in the following specific aims. Specific aim 1 will test the hypothesis that hypertension-induced inflammatory processes impair afferent arteriolar autoregulatory behavior in Ang II-infused hypertensive rats. Specific aim 2 will test the hypothesis that hypertension-induced inflammatory processes impair afferent arteriolar P2X1 receptor reactivity in Ang II-infused hypertensive rats. Specific aim 3 will test the hypothesis that MCP-1 contributes significantly to the hypertension induced afferent arteriolar dysfunction and impaired Ca2+ signaling mechanisms that occur in Ang II- infused hypertension. Specific aim 4 will test the hypothesis that hypertension-induced increases in TGF-2 and ROS contribute significantly to the decline in afferent arteriolar function. These studies will provide new mechanistic information linking chronic inflammatory events with suppression of autoregulatory function, impairment of Ca2+ signaling and renal microvascular reactivity to P2X receptor stimulation and they will demonstrate that suppression of inflammatory events leads to improved renal microvascular function and renal protection in hypertension. PUBLIC HEALTH RELEVANCE: This project focuses on determining the mechanisms involved in the autoregulatory and renal microvascular dysfunction that occurs in Ang II hypertension. Our preliminary work suggests a strong link to inflammation and inflammatory mediators playing a causal role in this renal vascular impairment. Understanding the impact of hypertension and inflammation on renal vascular function will provide unique insights capable of reducing hypertensive kidney injury.

描述（由申请人提供）：肾小球毛细管的升高是高血压肾脏损伤的主要危险因素。 ANG II高血压会损害自动调节并消除P2X1受体介导的血管收缩，这对于介导传入小动脉自动调节行为至关重要。高血压自动调节受损与肾细胞因子产生增加（例如TGF-2和MCP-1）一致，TGF-2和MCP-1可能涉及高血压诱导的肾脏微血管功能障碍。项目2将确定这些细胞因子对ANG II注入高血压的传入小动脉功能障碍的作用。初步数据表明，抗炎治疗可防止高血压传入的小动脉功能障碍。 TGF-2抑制自动调节反应。此外，用CCR2受体阻滞剂抑制MCP-1可提高高血压肾脏的自动调节效率。这些数据支持项目2的中心假设，即高血压引发肾内炎症事件，从而通过损害P2X1受体信号传导而导致传入小动脉功能障碍和肾脏损伤。注入ANG II的高血压大鼠将通过抗炎剂，五硫代硫酸盐或霉酚酸酯莫菲蒂尔治疗，以抑制炎症过程。实验将建立抗炎治疗对动脉自动调节行为受损的影响，降低传入的小动脉反应性，对P2受体刺激，前血液上的血管平滑肌CA2+信号传导以及ROS的表达和功能，ROS的功能以及经膜内部炎症介体以及高血压和正常的肿瘤的内部炎症介体。这些目标将在以下特定目标中解决。具体目标1将检验以下假设：高血压诱导的炎症过程会损害ANG II注入的高血压大鼠的传入小动脉自动调节行为。具体目标2将检验以下假设：高血压诱导的炎症过程会损害ANG II浸透的高血压大鼠的传入小动脉P2X1受体反应性。具体目标3将检验以下假设：MCP-1对高血压引起的传入小动脉功能障碍以及在ANG II-注入高血压中发生的CA2+信号传导机制受损。具体目标4将检验以下假设：高血压诱导的TGF-2和ROS的增加对传入小动脉功能的下降显着贡献。这些研究将提供新的机械信息，将慢性炎性事件与自动调节功能的抑制，CA2+信号传导的损害以及肾脏微血管反应性降低以及对P2X受体刺激的反应性，它们将证明炎症事件的抑制会导致肾脏微血管功能的改善和高血压的肾脏保护。公共卫生相关性：该项目致力于确定ANG II高血压中发生的自动调节和肾脏微血管功能障碍所涉及的机制。我们的初步工作表明，与炎症和炎症介质在这种肾血管损伤中起着因果作用有很强的联系。了解高血压和炎症对肾血管功能的影响将提供能够减少高血压肾脏损伤的独特见解。