Role of Organic Osmolytes in Renal Papillary Necrosis

有机渗透剂在肾乳头坏死中的作用

• 批准号: 7244260
• 负责人: GILBERT WOLFRAM MOECKEL
• 金额: $ 11.86万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7244260
• 关键词: Abbreviations; Address; Adenoviruses; Affect; Aldehyde Reductase; Analgesics; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Aspirin; Betaine; Canis familiaris; Cell Death; Cells; Condition; Consumption; Coxibs; Data; Dehydration; Development; Diagnostic Procedure; Dominant-Negative Mutation; Enhancers; Enzymes; Etiology; GABA transporter; Gene Expression; Genes; Glycerylphosphorylcholine; Goals; Health; High Pressure Liquid Chromatography; Human; I-kappa B Proteins; Impairment; In Vitro; Induction of Apoptosis; Ingestion; Injury; Inositol; Kidney; Kidney Diseases; Lead; Lesion; Link; Measures; Mediating; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Necrosis; Non-Prescription Drugs; Non-Steroidal Anti-Inflammatory Agents; Nuclear; PTGS2 gene; Papillary; Pathologic; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Preventive; Process; Property; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Protein Isoforms; Public Health; Regulation; Reporting; Research; Role; Signal Transduction; Societies; Sodium; Sorbitol; Stress; System; Testing; Therapeutic; Transcriptional Activation; Transcriptional Regulation; Tumor Necrosis Factor Ligand Superfamily Member 6; Urea; Work; activating transcription factor; base; cell injury; cofactor; cyclooxygenase 1; cyclooxygenase 2; design; diabetic; enhancer binding protein; in vivo; inhibitor/antagonist; insight; interstitial cell; kidney cell; mortality; multicatalytic endopeptidase complex; mutant; polyol; progesterone 11-hemisuccinate-(2-iodohistamine); response; trimethylamine

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.

描述（由申请人提供）： 镇痛肾病是许多西方社会的重要公共卫生问题。镇痛和非甾体类抗炎药（NSAIDS）的使用正在增加。这些药物，特别是NSAIDS的摄入与大量发病率和死亡率有关。肾乳头状坏死（RPN）是镇痛性肾病的标志性病变，是一个病理实体，尽管进行了深入研究，但仍被鲜为人知。拟议的研究的长期目标是阐明分子水平上RPN的病理机制。我们假设COX2抑制剂（即镇痛药和NSAIDS）在高渗条件下通过有机渗透渗漏的积累损害在高渗条件下导致肾脏髓质细胞死亡。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，通过COX2抑制和营救COX2抑制剂介导的渗透源细胞凋亡的降低了髓质肾细胞中细胞内渗透质的浓度。我们的假设将通过检查培养的小鼠髓质间质细胞（MMIC）在高渗条件下以及在小鼠髓质肾细胞下在脱水下的脱水（特定的目标1）中检查COX2抑制对渗透基因和渗透液转运蛋白的转录调节的影响（MMIC）。然后，我们将进步在同一模型中研究COX2抑制和有机渗透剂的抗凋亡特性的诱导机制（特定AIM 2）。最后，将定义细胞信号传导和核信号传导机制在COX2依赖性生存机制中的作用以及MMIC中渗透液积累的调节（特定目标3）。 RPN是一个病理性的实体，仍然知之甚少。该提案中的研究涉及我们对RPN的理解。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，以设计有效的诊断程序，治疗方法和RPN的预防措施。

项目成果

A woman with chronic hepatitis C infection and nephrotic syndrome who developed multiple renal lesions after interferon alfa therapy.

一名患有慢性丙型肝炎感染和肾病综合征的女性，在干扰素α治疗后出现多发性肾脏病变。

• 发表时间: 2004
• 期刊: American journal of kidney diseases : the official journal of the National Kidney Foundation.
• 作者: Fisher,MaxwellE;Rossini,Michele;Simmons,Edith;Harris,RaymondC;Moeckel,Gilbert;Zent,Roy
• 通讯作者: Zent,Roy