Glomerular COX-2 in Hypertensive Renal Disease

描述（由申请人提供）：慢性肾脏疾病（CKD）是一种与高发病率和死亡率相关的主要健康问题。高血压是CKD发展的主要危险因素。肾素血管紧张素系统（RAS）的适应性不良激活已被证明在包括高血压在内的不同病因的CKD发病机制中起关键作用。我们的长期目标是研究TGF-B。我们还假设COX-2来源的pc在高血压终末器官损伤，特别是肾损伤的发病机制中起主要作用。我们将追求以下具体目标：目的1：确定血管紧张素II （Ang II）诱导肾小球中COX-2表达和活性的机制。为了完成这一目标，我们将使用一系列体外和体内实验，旨在确定活性氧（ROS）和tgf - β作为肾小球COX-2表达的介质在Ang II反应中的作用。目的2：确定COX-2衍生的pc在肾素血管紧张素系统激活相关肾小球损伤发病机制中的作用。我们将确定COX-2阻断对Ang II在培养的系膜细胞中的促生长作用的影响，包括细胞外基质（ECM）沉积和系膜细胞增殖。此外，我们将确定COX-2在高血压达尔盐敏感大鼠（Ang II功能上调，ROS生成增加和严重终末器官损伤的模型）中的作用。我们将采用RT-PCR、western blot和免疫组化的方法检测高血压Dahl盐敏感大鼠肾小球中COX-2的表达，以及COX-2阻断对盐敏感高血压模型肾小球损伤的影响。这些研究结果将加深我们对RAS激活和COX-2在CKD发病机制中的作用的理解。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is a major health problem associated with a high morbidity and mortality. Hypertension is a major risk factor for the development of CKD. Maladpative activation of the renin angiotensin system (RAS) has been shown to play a critical role in the pathogenesis of CKD of different etiologies including hypertension. Our long term objective is to such as TGF-B. We also hypothesize that COX-2 derived PCs play a major role in the pathogenesis of end-organ injury in hypertension, specifically renal injury. We will pursue the following specific aims: Aim 1: To identify the mechanisms by which Angiotensin II (Ang II) induces COX-2 expression and activity in the glomerulus. To take this aim to completion we will use a series of in vitro and in vivo experiments aimed at determining the role of reactive oxygen species (ROS) and TGF-beta as mediators of the glomerular COX-2 expression in response to Ang II. Aim 2: To identify the role of COX-2 derived PCs in the pathogenesis of glomerular injury associated with activation of the renin angiotensin system. We will determine the effects of COX-2 blockade on the growth promoting effects of Ang II in cultured mesangial cells including extracellular matrix (ECM) deposition and mesangial cell proliferation. In addition, we will identify the role of COX-2 in the hypertensive Dahl salt sensituive rat rat, a model of functional upregulation of Ang II, increased ROS generation and severe end-organ injury. We will determine the glomerular expression of COX-2 in hypertensive Dahl salt sensitive rats (RT-PCR, western blot and immunohistochemistry) as well as the effects of COX-2 blockade on glomerular injury in this model of salt sensitive hypertension. Results from these studies will enhance our understanding of the role of RAS activation and COX-2 in the pathogenesis of CKD.