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: 7614967
• 负责人: DIDIER PORTILLA
• 金额: $ 22.78万
• 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/7614967
• 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; Predisposition; Prevention; Proteins; Reperfusion Injury; Reperfusion Therapy; Research Personnel; Respiratory physiology; Response Elements; Role; Tokyo; 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; 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（由申请人提供）：我们之前的研究已经提供了底物氧化抑制与近端小管细胞死亡发展之间的因果关系。过氧化物酶体增殖物激活受体-α (PPARa) 在肾脏中表达，更具体地说在近曲小管中表达，并刺激许多参与脂质代谢的基因的表达，例如肝脏脂肪酸结合蛋白 (L-FABP)。在我们的研究中，我们发现贝特类药物上调 PPARa 活性可防止脂肪酸氧化的抑制，并导致近曲小管细胞死亡显着减少并预防器官功能障碍，而 PPARa 基因缺失会增加肾脏对缺血再灌注和顺铂诱导的 ARF 的易感性。我们最近使用肾雄激素调节启动子 (KAP2)-PPARa 转基因小鼠进行的研究表明，这些小鼠在近曲小管中表达较高水平的 PPARa，可以保护这些小鼠免受顺铂和缺血/再灌注诱导的急性肾衰竭 (ARF) 的影响，类似于我们之前在接受贝特类药物治疗的野生型小鼠中所描述的情况。我们的第一个假设是 PPARa 激活可防止近曲小管细胞死亡，并通过增加近曲小管中的 FFA 改善 ARF。我们的第一个具体目标是研究 PPARa 激活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 表达的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 在急性肾衰竭体内和体外模型中的作用。我们将检查人 L-FABP 转基因小鼠近曲小管中 L-FABP 表达的增加是否在 ARF 期间赋予细胞保护作用。最后，我们将检查近曲小管 L-FABP 表达增加具有细胞保护作用的细胞机制。贝特类药物在急性肾功能衰竭期间的保护作用非常显着，未来研究可考虑将其用于临床试验，以改善急性肾损伤并降低死亡率。