Role of COX2 in Medullary Interstitial Cell Survival and Function

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DESCRIPTION (provided by applicant): Hypertension is an important public health problem and one of the major causes of morbidity and mortality in all western societies. Several studies have emphasized the importance of the renal medullary blood flow in long term regulation of blood pressure. Medullary blood flow is regulated by eicosanoids such as prostaglandins, which are produced in the medulla and act locally. The medullary interstitial cell (MIC) is the predominant site of medullary prostanoid production. Prostanoid-dependent cell survival mechanisms, such as organic osmolyte accumulation, protect cells in the renal medulla against hyperosmotic stress. We hypothesize that impairment of prostanoid-dependent MIC survival leads to decrease in medullary blood flow and rise in arterial blood pressure. Our hypothesis is based on our exciting in vivo and in vitro data that show that inhibition of renal prostaglandin synthesis leads to both impairment of medullary interstitial cell survival and medullary blood flow. However, the exact mechanisms how prostanoids mediate osmolyte accumulation and how these ameliorate hypertonic stress-induced injury to medullary interstitial cells is unknown. We will test our hypothesis by examining the mechanisms that lead to hypertonicity-induced cell death, and how osmolyte prevent mitochondrial injury under hyperosmotic conditions, (specific aim 1). We will then progress to investigate the role of Src family kinases (SFKs) on hypertonicity-induced signaling that mediates increased prostanoid synthesis (COX2) and osmolyte accumulation (TonEBP/NFAT5) (specific aim 2). Finally, we will examine the role of the prostaglandin E protein receptor (EP3), which is highly prevalent in the medulla, on osmolyte transport regulation and cell survival in vivo and in vitro (specific aim 3). The mechanisms that regulate medullary blood flow and the role of the medullary interstitial cell in long term blood pressure regulation are poorly understood. The studies in this proposal address this major gap in our understanding. Our long term goals are to gain insight into the mechanistic process that leads to the important health problem of hypertension. It is necessary to understand these processes in order to design effective therapeutic approaches and develop new drugs to treat hypertension. High blood pressure is a common health problem and a major cause of heart attack and stroke in western societies. Several studies have shown the importance of good blood flow to the kidney for the maintenance of low blood pressure. Certain kidney cells are super-regulators of blood flow and their survival is highly important to keep blood pressure low. The goals of this study are to understand better how these super-regulator cells survive and keep blood pressure low. It is necessary to understand how these cells function in order to design better drugs to treat high blood pressure.