Role of PPARalpha and L-FABP in Acute Renal Failure

描述(由申请人提供)：我们以前的研究已经提供了抑制底物氧化和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，更具体地说在近曲小管中表达，并刺激许多与脂质代谢有关的基因的表达，如和肝脏脂肪酸结合蛋白(L-FABP)。在我们的研究中，我们的研究表明，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。我们最新的研究使用肾雄激素调节启动子(KAP2)-PPARa转基因小鼠，在近端小管中表达更高水平的PPARa，我们发现这些小鼠可以免受顺铂和缺血/再灌注引起的急性肾功能衰竭(ARF)的保护，类似于我们之前在使用贝特类药物治疗的野生型小鼠中所描述的那样。我们的第一个假设是，PPARa激活防止了近端小管细胞死亡，并通过增加近端小管中的FAO来改善ARF。我们的第一个特定目标是研究PPARa激活阻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的高表达通过减少氧化应激和非酯化脂肪酸的积累而起到细胞保护作用。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。我们将检测在人类L-FABP转基因小鼠的近曲小管中，L-FABP的表达增加是否在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非常显著，可在未来的研究中考虑将其用于临床试验，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.