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

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• 作者：L. Jay Stallons ; Ryan M. Whitaker ; Rick G. Schnellmann
• 关键词：Acute kidney injury ; Mitochondrial biogenesis ; Fibrosis ; Folic acid
• 刊名：Toxicology Letters
• 出版年：30 January, 2014
• 年：2014
• 卷：224
• 期：3
• 页码：326-332
• 全文大小：1608 K

文摘

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 4 d. In contrast, peroxisome proliferator gamma coactivator 1伪 (PGC-1伪) and mitochondrial transcription factor A (TFAM), critical transcriptional regulators of mitochondrial biogenesis (MB), were down-regulated 鈭?0% 1 d 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尾8), ATP synthase subunit 尾 (ATPS-尾), and cytochrome C oxidase subunit I (COXI). Mitochondrial DNA copy number was reduced 鈭?0% from 2 to 14 d after FA injection. Protein levels of early fibrosis markers 伪-smooth muscle actin and transforming growth factor 尾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.