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

描述（由申请人提供）：肾小球毛细血管压升高是高血压肾损伤的主要危险因素。血管紧张素II高血压损害自动调节并消除P2 X1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。高血压自身调节功能受损与肾脏细胞因子产生增加相一致，如TGF-2和MCP-1，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对血管紧张素II输注高血压的传入小动脉功能障碍的作用。初步数据表明，抗炎治疗可预防高血压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CCR 2受体阻断提高高血压肾的自动调节效率。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，通过损害P2 X1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灌注的高血压大鼠将用抗炎剂戊聚糖多硫酸酯或霉酚酸酯治疗，以抑制炎症过程。实验将确定抗炎治疗对高血压和血压正常大鼠中受损的小动脉自动调节行为、降低的传入小动脉对P2受体刺激的反应性、肾小球前血管平滑肌Ca 2+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加以阐述。具体目标1将测试的假设，即高血压诱导的炎症过程损害血管紧张素II输注高血压大鼠的传入小动脉自动调节行为。具体目标2将测试的假设，即高血压诱导的炎症过程损害传入小动脉P2 X1受体的反应性在血管紧张素II输注高血压大鼠。具体目标3将检验MCP-1显著促进高血压诱导的传入小动脉功能障碍和在Ang II灌注的高血压中发生的受损的Ca 2+信号传导机制的假设。具体目标4将检验高血压诱导的TGF-2和ROS增加显著导致传入小动脉功能下降的假设。这些研究将提供新的机制信息，将慢性炎症事件与自身调节功能抑制、Ca 2+信号传导受损和肾微血管对P2 X受体刺激的反应性联系起来，并且它们将证明炎症事件的抑制导致高血压中肾微血管功能改善和肾保护。

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.