Suppressed Mitochondrial Biogenesis in Folic Acid-induced Acute Kidney Injury and Early Fibrosis
Overview
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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 1α (PGC-1α) 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 (NDUFβ8), ATP synthase subunit β (ATPS-β), 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 α-smooth muscle actin and transforming growth factor β1 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.
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