Blood brain barrier (BBB) disruption plays an important role in brain injury after acute kidney injury (AKI). However, its underlying mechanisms remain poorly understood. Recent evidence has revealed that proper mitochondrial function is essential for BBB permeability. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is a key factor in mitochondrial biogenesis and function. This study was designed to investigate the role of PGC-1 alpha in BBB injury after AKI and its related mechanisms. Mice received recombinant adenovirus encoding murine PGC-1 alpha (100 mu l, 1.0 x 10(9)PFU/ml) or vehicle 5 days before renal I/R or sham operation. Twenty-four hours after the operation, brain, kidney and serum samples were collected for assessments. We found that mice suffering from renal I/R injury showed decreased PGC-1 alpha levels in both the kidney and BBB. PGC-1 alpha transfection resulted in increased PGC-1 alpha level and mitochondrial transcripts in BBB at 24 h after AKI. PGC-1 alpha transfection improved renal function, systemic inflammation and BBB permeability via both the paracellular and transcellular pathways. Further study suggested that PGC-1 alpha overexpression elevated fatty acid oxidation related gene expression. Our findings demonstrate the importance of PGC-1 alpha in AKI-induced BBB injury and suggest that it could be a therapeutic target for BBB repair via the regulation of mitochondrial function.