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.
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