Role of Organic Osmolytes in Renal Papillary Necrosis

描述(由申请人提供)： 在许多西方社会，止痛性肾病是一个重要的公共卫生问题。止痛药和非类固醇抗炎药(NSAIDs)的使用正在增加。摄入这些药物，特别是非甾体抗炎药，与严重的发病率和死亡率有关。肾乳头状坏死(RPN)是止痛性肾病的标志性病变，尽管进行了深入的研究，但对其病理实体仍知之甚少。这些研究的长期目标是在分子水平上阐明RPN的病理机制。我们假设COX2抑制剂(即镇痛剂和非甾体类抗炎药)在高渗条件下通过损害有机渗透压积聚而导致肾髓质细胞死亡。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，COX2抑制和修复COX2抑制剂介导的细胞凋亡可以降低髓质肾细胞内渗透压的浓度。我们的假设将通过检测COX2抑制对高渗条件下培养的小鼠骨髓间质细胞(MMICs)以及体内脱水小鼠骨髓肾细胞中渗透压基因转录调控和渗透压转运体活性的影响来检验(特定目标1)。然后，我们将在相同的模型中研究COX2抑制诱导细胞凋亡的机制和有机渗透调节物质的抗凋亡特性(特定目标2)。最后，将确定细胞信号和核信号机制在依赖COX2的生存机制和MMICs中渗透调节物质积累中的作用(具体目标3)。RPN是一种病理实体，目前仍知之甚少。本提案中的研究解决了我们对RPN理解中的这一主要差距。我们的长期目标是深入了解导致这一重要健康问题的机械过程。有必要了解这些过程，以便设计有效的RPN诊断程序、治疗方法和预防措施。

DESCRIPTION (provided by applicant): Analgesic nephropathy is an important public health problem in many Western societies. The use of analgesic and non-steroidal anti-inflammatory drugs (NSAIDs) is increasing. The ingestion of these agents, particularly NSAIDs, has been associated with significant morbidity and mortality. Renal Papillary Necrosis (RPN), the hallmark lesion of analgesic nephropathy, is a pathologic entity that is still poorly understood despite intensive research. The long-term goal of the proposed studies is to elucidate the pathologic mechanisms involved in RPN at the molecular level. We hypothesize that COX2 inhibitors (i.e. analgesics and NSAIDs) contribute to renal medullary cell death under hypertonic conditions through impairment of organic osmolyte accumulation. Our hypothesis is based on our exciting in vivo and in vitro data that show reduction of intracellular osmolyte concentrations in medullary kidney cells by COX2 inhibition and rescue of COX2 inhibitor-mediated apoptosis by osmolytes. Our hypothesis will be tested by examining the impact of COX2 inhibition on transcriptional regulation of osmolyte genes and osmolyte transporter activities in cultured mouse medullary interstitial cells (mMICs) under hypertonic conditions, as well as in mouse medullary kidney cells under dehydration in vivo (specific aim 1). We will then progress to investigate in the same model the induction mechanisms of apoptosis by COX2 inhibition and the antiapoptotic properties of organic osmolytes (specific aim 2). Finally, the role of cell signaling and nuclear signaling mechanisms involved in COX2- dependent survival mechanisms and regulation of osmolyte accumulation in mMICs will be defined (specific aim 3). RPN is a pathologic entity that is still poorly understood. The studies in this proposal address this major gap in our understanding of RPN. Our long-term goals are to gain insight into mechanistic processes that lead to this important health problem. It is necessary to understand these processes in order to design effective diagnostic procedures, therapeutic approaches and preventive measures for RPN.