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

描述(申请人提供)：肾小球毛细血管压力升高是高血压肾损伤的主要危险因素。Ang II高血压损害自身调节，并消除P2X1受体介导的血管收缩，这对调节传入小动脉的自身调节行为至关重要。高血压患者自身调节功能受损的同时，肾脏细胞因子如转化生长因子-2和单核细胞趋化蛋白-1的产生增加，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在血管紧张素II灌注性高血压患者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患者的传入小动脉功能障碍。转化生长因子-2抑制自身调节反应。此外，用CCR2受体阻断抑制MCP-1可提高高血压肾脏的自我调节效率。这些数据支持项目2的中心假设，即高血压通过损害P2X1受体信号而引发肾内炎症事件，导致传入小动脉功能障碍和肾脏损伤。血管紧张素转换酶II注入的高血压大鼠将接受抗炎药多硫酸戊聚糖或霉酚酸酯的治疗，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受损的小动脉自主调节行为、对P2受体刺激的传入小动脉反应性降低、肾小球前血管平滑肌钙信号转导机制以及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将验证高血压诱导的炎症过程损害血管紧张素-II注入的高血压大鼠的传入小动脉自我调节行为的假说。特定目的2将验证高血压诱导的炎症过程损害血管紧张素Ⅱ注入的高血压大鼠的传入小动脉的P2X1受体反应性的假说。具体目标3将验证MCP-1在高血压引起的传入小动脉功能障碍和Ang II灌注性高血压中发生的钙信号机制受损中起重要作用的假设。具体目标4将检验高血压引起的转化生长因子-2和ROS的增加对传入小动脉功能下降有显著贡献的假设。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的抑制、钙信号的损害以及肾微血管对P2X受体刺激的反应性联系起来，并将证明抑制炎症事件导致高血压时肾脏微血管功能的改善和肾脏保护。 公共卫生相关性：该项目侧重于确定发生在Ang II高血压中的自我调节和肾微血管功能障碍的机制。我们的初步工作表明，炎症和炎症介质在肾血管损伤中起着因果作用，这与炎症和炎症介质有很强的联系。了解高血压和炎症对肾血管功能的影响将为减少高血压肾损伤提供独特的见解。

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.