Role of PPARalpha and L-FABP in Acute Renal Failure

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，更具体地在近端小管中表达，并刺激许多参与脂质代谢的基因的表达，如，和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活性可以阻止脂肪酸氧化的抑制，并显著减少近端小管细胞死亡和防止器官功能障碍，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。我们最近对肾雄激素调节启动子(KAP2)-PPARa转基因小鼠的研究表明，这些小鼠在近端小管中表达更高水平的PPARa，我们表明这些小鼠免受顺铂和缺血/再灌注诱导的急性肾功能衰竭（ARF）的影响，类似于我们之前在使用贝特类药物治疗的野生型小鼠中描述的情况。我们的第一个假设是，PPARa激活可以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）的核易位。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期间提供细胞保护。最后，我们将研究近端小管L-FABP表达增加具有细胞保护作用的细胞机制。贝特在急性肾功能衰竭时的保护作用是非常显著的，在未来的研究中可以考虑在临床试验中使用贝特，以改善急性肾损伤，降低死亡率。

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.