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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

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

Stallons L Jay LJ Whitaker Ryan M RM Schnellmann Rick G RG

Toxicology letters 20131122 3

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 coact ...[more]

PMID: 24275386

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Project description:Rationale & Objective:Uric acid is excreted by the kidney and accumulates in acute kidney injury (AKI). Whether higher plasma uric acid level predisposes to AKI or its complications is not known. Study Design:Prospective observational cohort study. Setting & Participants:2 independent cohorts of critically ill patients: (1) 208 patients without AKI admitted to the intensive care unit (ICU) at Brigham & Women's Hospital between October 2008 and December 2016; and (2) 250 participants with AKI requiring renal replacement therapy (RRT) who had not yet initiated RRT enrolled in the Acute Renal Failure Trial Network (ATN) Study. Exposure:Plasma uric acid level upon ICU admission and before RRT initiation in the ICU and ATN Study cohorts, respectively. Outcomes:Incident AKI and 60-day mortality in the ICU and ATN Study cohorts, respectively. Analytical Approach:Logistic regression models were used to test the association of plasma uric acid level with incident AKI and 60-day mortality. Results:In the ICU cohort, median plasma uric acid level was 4.7 (interquartile range [IQR], 3.6-6.4) mg/dL, and 40 patients (19.2%) developed AKI. Higher plasma uric acid levels associated with incident AKI, but this association was confounded by serum creatinine level and was not significant after multivariable adjustment (adjusted OR per doubling of uric acid, 1.50; 95% CI, 0.80-2.81). In the ATN Study cohort, median plasma uric acid level was 11.1 (IQR, 8.6-14.2) mg/dL, and 125 participants (50.0%) died within 60 days. There was no statistically significant association between plasma uric acid levels and 60-day mortality in either unadjusted models or after multivariable adjustment for demographic, severity-of-illness, and kidney-specific covariates (adjusted OR per doubling of uric acid, 1.15; 95% CI, 0.71-1.86). Limitations:Heterogeneity of ICU patients. Conclusions:Plasma uric acid levels upon ICU admission or before RRT initiation are not independently associated with adverse clinical outcomes in critically ill patients.

Dataset Information

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

Publications

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

Similar Datasets

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