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）的异常激活已被证明在包括高血压在内的不同病因的CKD的发病机制中起关键作用。我们的长期目标是如TGF-B。我们还推测考克斯-2衍生的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）诱导肾小球考克斯-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作为肾小球考克斯-2表达的介导剂对Ang II的反应。目的2：研究考克斯-2衍生的前体细胞在肾小球损伤中的作用。我们将确定考克斯-2阻断对血管紧张素II在培养的系膜细胞中的生长促进作用的影响，包括细胞外基质（ECM）沉积和系膜细胞增殖。此外，我们将确定考克斯-2在高血压Dahl盐敏感大鼠中的作用，这是一种Ang II功能上调、ROS产生增加和严重终末器官损伤的模型。我们将通过RT-PCR、免疫印迹和免疫组化等方法检测考克斯-2在高血压盐敏感大鼠肾小球中的表达，并观察考克斯-2阻断剂对盐敏感性高血压大鼠肾小球损伤的影响。这些研究的结果将加深我们对RAS激活和考克斯-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.