title: 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 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.
authors.affiliation: Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 280 Calhoun Street, Charleston, SC 29425, USA. Electronic address: stallons@musc.edu.
authors.forename: L Jay
authors.initials: LJ
authors.lastname: Stallons
authors.affiliation: Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 280 Calhoun Street, Charleston, SC 29425, USA. Electronic address: whitakr@musc.edu.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Whitaker
authors.affiliation: Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, 280 Calhoun Street, Charleston, SC 29425, USA; Ralph H. Johnson Veterans Affairs Medical Center, 109 Bee Street, Charleston, SC 29401, USA. Electronic address: schnell@musc.edu.
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
mesh_terms: D000199:Actins / Q000096:biosynthesis; D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism; D003404:Creatinine / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D003576:Electron Transport Complex IV / Q000378:metabolism; D005355:Fibrosis; D005492:Folic Acid / Q000633:toxicity*; D006029:Glycosuria / Q000139:chemically induced; D006397:Hematinics / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000199:Actins; D006397:Hematinics; D012333:RNA, Messenger; D003094:Collagen; D004247:DNA; D005492:Folic Acid; D003404:Creatinine; D003576:Electron Transport Complex IV
keywords: Acute kidney injury; Fibrosis; Folic acid; Mitochondrial biogenesis