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Nat Med. 2015 Jan;21(1):37-46. doi: 10.1038/nm.3762. Epub 2014 Dec 1.

Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.

Author information

1
Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
2
Division of Nephrology, Department of Medicine, University of California, San Diego, Veterans Administration San Diego HealthCare System, La Jolla, California, USA.
3
Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.
4
Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
5
Department of Medicine, New York University Langone Medical Center, New York, New York, USA.

Abstract

Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large cohort (n = 95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses and identified inflammation and metabolism as the top dysregulated pathways in the diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and higher intracellular lipid deposition compared to controls. In vitro experiments indicated that inhibition of FAO in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition, phenotypes observed in fibrosis. In contrast, restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.

PMID:
25419705
PMCID:
PMC4444078
DOI:
10.1038/nm.3762
[Indexed for MEDLINE]
Free PMC Article

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