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

L. Jay Stallons, Ryan M. Whitaker, Rick G. Schnellmann

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

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 4. d. 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% 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 (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.

Original languageEnglish (US)
Pages (from-to)326-332
Number of pages7
JournalToxicology letters
Volume224
Issue number3
DOIs
StatePublished - Jan 30 2014
Externally publishedYes

Keywords

  • Acute kidney injury
  • Fibrosis
  • Folic acid
  • Mitochondrial biogenesis

ASJC Scopus subject areas

  • Toxicology

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