Role of COX2 in Medullary Interstitial Cell Survival and Function

描述（由申请人提供）： 高血压是一个重要的公共卫生问题，是所有西方社会发病率和死亡率的主要原因之一。一些研究强调了肾髓质血流在血压长期调节中的重要性。髓血流量由类花生酸（如胡萝卜素）调节，类花生酸在髓中产生并在局部起作用。髓质间质细胞（MIC）是髓质前列腺素类产生的主要部位。前列腺素依赖性细胞存活机制，如有机渗透压物质蓄积，保护肾髓质细胞免受高渗应激。我们假设前列腺素依赖性MIC存活受损导致髓质血流量减少和动脉血压升高。我们的假设是基于我们令人兴奋的体内和体外数据，这些数据表明抑制肾前列腺素合成导致髓质间质细胞存活和髓质血流受损。然而，前列腺素类如何介导渗透压蓄积以及这些如何改善高渗应激诱导的髓质间质细胞损伤的确切机制尚不清楚。我们将通过检查导致高渗诱导的细胞死亡的机制以及渗透剂如何在高渗条件下防止线粒体损伤来验证我们的假设（具体目的1）。然后，我们将研究Src家族激酶（SFKs）在高渗诱导的信号传导中的作用，该信号传导介导前列腺素合成（COX 2）和渗透压物质积累（TonEBP/NFAT 5）增加（具体目标2）。最后，我们将研究前列腺素E蛋白受体（EP 3）的作用，这是非常普遍的髓质，渗透调节和细胞存活在体内和体外（具体目标3）。对调节髓质血流的机制和髓质间质细胞在长期血压调节中的作用知之甚少。本提案中的研究解决了我们认识上的这一重大差距。我们的长期目标是深入了解导致高血压这一重要健康问题的机制过程。为了设计有效的治疗方法和开发治疗高血压的新药，有必要了解这些过程。高血压是一种常见的健康问题，也是西方社会心脏病发作和中风的主要原因。一些研究表明，良好的血液流向肾脏对于维持低血压的重要性。某些肾细胞是血流的超级调节器，它们的存活对于保持低血压非常重要。这项研究的目的是更好地了解这些超级调节细胞如何生存并保持低血压。有必要了解这些细胞的功能，以便设计更好的药物来治疗高血压。

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.