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

ABSTRACT: 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 2 d after injection that resolved by 4d. In contrast, peroxisome proliferator gamma coactivator 1? (PGC-1?) and mitochondrial transcription factor A (TFAM), critical transcriptional regulators of mitochondrial biogenesis (MB), were down-regulated ?80% 1d after FA injection and remained depressed through 14 d. Multiple electron transport chain and ATP synthesis genes were also down-regulated from 1 to 14 d after FA, including NADH dehydrogenase (ubiquinone) 1 beta subcomplex 8 (NDUF?8), ATP synthase subunit ? (ATPS-?), and cytochrome C oxidase subunit I (COXI). Mitochondrial DNA copy number was reduced ?50% from 2 to 14 d after FA injection. Protein levels of early fibrosis markers ?-smooth muscle actin and transforming growth factor ?1 were elevated at 6 and 14 d after FA. Picrosirius red staining and collagen 1A2 (COL1A2) IHC revealed staining for mature collagen deposition at 14 d. 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.

SUBMITTER: Stallons LJ 

PROVIDER: S-EPMC3987699 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature