Role of PPARalpha and L-FABP in Acute Renal Failure

PPARα 和 L-FABP 在急性肾衰竭中的作用

• 批准号: 7261588
• 负责人: DIDIER PORTILLA
• 金额: $ 22.61万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7261588
• 关键词: Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Affect; Androgens; Apoptosis; Apoptotic; Cell Death; Cells; Cessation of life; Cisplatin; Clinical Trials; Collaborations; Cytochromes; Cytoprotection; Development; Enzymes; Epithelial Cells; Esterified Fatty Acids; Exhibits; Fatty Acid-Binding Protein 1; Fatty Acids; Fibrates; Functional disorder; Future; Genes; Genetic; Glucose; Human; Ischemia; Kidney; Ligands; Mediating; Metabolism; Mitochondria; Modeling; Morbidity - disease rate; Mus; Necrosis; Nonesterified Fatty Acids; Nuclear Translocation; Organ; Oxidative Stress; PPAR alpha; Patients; Physiological reperfusion; Predisposition; Prevention; Proteins; Reperfusion Injury; Reperfusion Therapy; Research Personnel; Respiratory physiology; Response Elements; Role; Tokyo; Transcriptional Activation; Transgenic Mice; Universities; Up-Regulation; Wild Type Mouse; anaerobic glycolysis; apoptosis inducing factor; cell injury; endonuclease G; fatty acid oxidation; in vitro Model; in vivo; in vivo Model; lipid metabolism; liver fatty acid-binding protein; mortality; oxidation; prevent; programs; promoter; protective effect; research study

DESCRIPTION (provided by applicant): Our previous studies have provided a causal relationship between inhibition of substrate oxidation and the development of proximal tubule cell death. Peroxisome proliferator activated receptor-alpha (PPARa) is expressed in the kidney and more specifically in the proximal tubule, and stimulates the expression of many genes involved in lipid metabolism, such as, and liver fatty acid binding protein (L-FABP). In our studies we have shown that upregulation of PPARa activity by fibrates prevents the inhibition of fatty acid oxidation, and resulted in significant reduction in proximal tubule cell death and prevention of organ dysfunction, whereas genetic deletion of PPARa increased kidney susceptibility to ischemia reperfusion and cisplatin induced ARF. Our most recent studies using kidney androgen regulated promoter (KAP2)-PPARa transgenic mice that express higher levels of PPARa in the proximal tubule we show that these mice are protected from cisplatin and ischemia/reperfusion induced acute renal failure (ARF), similarly to what we have previously described in wild type mice treated with fibrates. Our first hypothesis is that PPARa activation prevents proximal tubule cell death and ameliorates ARF by increasing FAO in the proximal tubule. Our first specific aim will examine the mechanisms by which PPARa activation prevents proximal tubule cell death including changes in mitochondrial respiratory function, expression of uncoupling proteins, changes in cellular metabolism, and preventing nuclear translocation of Apoptotic inducing factor (AIF). Our second hypothesis is that increased expression of L-FABP is cytoprotective by reducing oxidative stress and accumulation of nonesterified fatty acids. Our second aim will examine the role of L-FABP in in vivo and in vitro models of acute renal failure. We will examine whether increased expression of L-FABP in the proximal tubule in human L-FABP transgenic mice confers cytoprotection during ARF. Finally we will examine cellular mechanisms by which increased expression of proximal tubule L-FABP is cytoprotective. The protective effect provided by fibrate administration during acute renal failure is very significant, and its use in clinical trials could be considered in future studies, in order to ameliorate acute kidney injury and reduce mortality.

描述（由申请方提供）：我们之前的研究提供了底物氧化抑制与近端小管细胞死亡之间的因果关系。过氧化物酶体增殖物激活受体-α（PPARa）在肾脏中表达，更具体地在近端小管中表达，并刺激参与脂质代谢的许多基因的表达，例如，和肝脂肪酸结合蛋白（L-FABP）。在我们的研究中，我们已经表明，通过贝特类药物上调PPARa活性阻止了脂肪酸氧化的抑制，并导致近端小管细胞死亡的显著减少和器官功能障碍的预防，而PPARa的基因缺失增加了肾脏对缺血再灌注和顺铂诱导的ARF的易感性。我们最近使用在近端小管中表达更高水平的PPARa的肾雄激素调节启动子（KAP 2）-PPARa转基因小鼠的研究表明，这些小鼠受到保护免于顺铂和缺血/再灌注诱导的急性肾衰竭（ARF），类似于我们先前在用贝特类治疗的野生型小鼠中所描述的。我们的第一个假设是，PPARa激活防止近端小管细胞死亡，并通过增加近端小管中的FAO来改善ARF。我们的第一个具体目标将检查PPARa活化防止近端小管细胞死亡的机制，包括线粒体呼吸功能的变化、解偶联蛋白的表达、细胞代谢的变化以及防止凋亡诱导因子（AIF）的核转位。我们的第二个假设是L-FABP的表达增加通过减少氧化应激和非酯化脂肪酸的积累而具有细胞保护作用。我们的第二个目标是研究L-FABP在体内和体外急性肾功能衰竭模型中的作用。我们将研究在人L-FABP转基因小鼠近端小管中L-FABP表达的增加是否在ARF期间赋予细胞保护作用。最后，我们将研究近端小管L-FABP表达增加的细胞保护机制。贝特类药物在急性肾功能衰竭期间提供的保护作用非常显著，在未来的研究中可以考虑将其用于临床试验，以改善急性肾损伤并降低死亡率。