The cytokines, MCP-1 and TGF-beta, mediate renal autoregulatory impairment

细胞因子 MCP-1 和 TGF-β 介导肾脏自动调节功能障碍

• 批准号: 8900028
• 负责人: Edward W Inscho
• 金额: $ 12.73万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-04 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900028
• 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; Health; Homeostasis; Hydrogen Peroxide; Hypertension; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Injury; Kidney; Left; Link; Mediating; Mediator of activation protein; Microvascular Dysfunction; P2X-receptor; Pentosan Polysulfate; Play; Process; Production; Property; Rattus; Reactive Oxygen Species; Receptor Activation; Receptor Signaling; Renal function; 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; receptor; research study; response; transmission process; vasoconstriction

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.

描述（由申请人提供）：肾小球毛细血管压力升高是高血压性肾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的自动调节行为至关重要。高血压的自身调节受损与肾脏细胞因子的产生增加同时发生，例如TGF-2和MCP-1，这可能与高血压引起的肾微血管功能障碍有关。项目 2 将确定这些细胞因子对 Ang II 输注性高血压中传入小动脉功能障碍的作用。初步数据表明，抗炎治疗可预防高血压患者的传入小动脉功能障碍。 TGF-2 抑制自身调节反应。此外，MCP-1 抑制与 CCR2 受体阻断可提高高血压肾脏的自身调节效率。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，通过损害 P2X1 受体信号传导导致传入小动脉功能障碍和肾损伤。血管紧张素II输注的高血压大鼠将接受抗炎剂、多硫酸戊聚糖或吗替麦考酚酯治疗，以抑制炎症过程。实验将确定抗炎治疗对高血压和正常血压大鼠小动脉自动调节行为受损、传入小动脉对 P2 受体刺激的反应性降低、肾小球前血管平滑肌 Ca2+ 信号传导机制以及 ROS 和肾内炎症介质的表达和功能的影响。这些目标将在以下具体目标中得到解决。具体目标 1 将检验以下假设：高血压诱导的炎症过程损害血管紧张素 II 输注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输注 Ang II 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和 Ang II 输注高血压中发生的 Ca2+ 信号传导机制受损有显着贡献。具体目标 4 将检验以下假设：高血压引起的 TGF-2 和 ROS 增加显着导致传入小动脉功能下降。这些研究将提供新的机制信息，将慢性炎症事件与自动调节功能抑制、Ca2+信号传导受损以及肾微血管对 P2X 受体刺激的反应性联系起来，并将证明炎症事件的抑制可改善高血压患者的肾微血管功能和肾脏保护。