Glomerular COX-2 in Hypertensive Renal Disease

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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.