Suppressed mitochondrial biogenesis in folic acid-induced acute kidney injury and early fibrosis

Acute kidney injury (AKI) is a disease with mitochondrial dysfunction and a newly established risk factor for the development of chronic kidney disease (CKD) and fibrosis. We examined mitochondrial homeostasis in the folic acid (FA)-induced AKI model that develops early fibrosis over a rapid time course. Mice given a single dose of FA had elevated serum creatinine (3-fold) and urine glucose (2.2-fold) 1 and 2d after injection that resolved by 4d. In contrast, peroxisome proliferator gamma coactivator 1 alpha(PGC-1 alpha) and mitochondrial transcription factor A (TFAM), critical transcriptional regulators of mitochondrial biogenesis (MB), were down-regulated similar to 80% 1d after FA injection and remained depressed through 14d. Multiple electron transport chain and ATP synthesis genes were also down-regulated from 1 to 14d after FA, including NADH dehydrogenase (ubiquinone) 1 beta subcomplex 8 (NDUF beta 8), ATP synthase subunit beta (ATPS-beta), and cytochrome C oxidase subunit I (COXI). Mitochondrial DNA copy number was reduced similar to 50% from 2 to 14d after FA injection. Protein levels of early fibrosis markers alpha-smooth muscle actin and transforming growth factor beta 1 were elevated at 6 and 14d after FA. Picrosirius red staining and collagen 1A2 (COL1A2) IHC revealed staining for mature collagen deposition at 14d. We propose that mitochondrial dysfunction induced by AKI is a persistent cellular injury that promotes progression to fibrosis and CKD, and that this model can be used to test mitochondrial therapeutics that limit progression to fibrosis and CKD. Published by Elsevier Ireland Ltd.