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

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型高血压损害自身调节并消除P2X1受体介导的血管收缩，而P2X1受体介导的血管收缩对于调节传入小动脉自身调节行为至关重要。高血压患者自身调节功能受损与肾细胞因子（如TGF-2和MCP-1）产生增加相一致，这可能与高血压诱导的肾微血管功能障碍有关。项目2将确定这些细胞因子在angii输注高血压传入小动脉功能障碍中的作用。初步数据表明，抗炎治疗可预防高血压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受体信号导致传入小动脉功能障碍和肾损伤。用抗炎药聚硫酸戊糖或霉酚酸酯治疗ⅱ型高血压大鼠，以抑制炎症过程。实验将建立抗炎治疗对高血压和正常血压大鼠小动脉自身调节行为受损、传入小动脉对P2受体刺激反应性降低、肾小球前血管平滑肌Ca2+信号机制以及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加以解决。特异性目的1将检验高血压诱导的炎症过程损害angii输注高血压大鼠传入小动脉自身调节行为的假设。特异性目的2将验证高血压诱导的炎症过程损害angii输注高血压大鼠传入小动脉P2X1受体反应性的假设。特异性目的3将验证MCP-1在angii输注高血压中引起的高血压传入小动脉功能障碍和Ca2+信号机制受损的假设。特异性目的4将验证高血压诱导的TGF-2和ROS的增加对传入小动脉功能下降有重要作用的假设。这些研究将提供新的机制信息，将慢性炎症事件与抑制自身调节功能、Ca2+信号损伤和肾微血管对P2X受体刺激的反应性联系起来，并将证明抑制炎症事件可改善高血压患者的肾微血管功能和肾脏保护。

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.