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

Hyun Mi Kang, Seon Ho Ahn, Peter Choi, Yi An Ko, Seung Hyeok Han, Frank Chinga, Ae Seo Deok Park, Jianling Tao, Kumar Sharma, James Pullman, Erwin P. Bottinger, Ira J. Goldberg, Katalin Susztak

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297 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)37-46
Number of pages10
JournalNature Medicine
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Kang, H. M., Ahn, S. H., Choi, P., Ko, Y. A., Han, S. H., Chinga, F., Park, A. S. D., Tao, J., Sharma, K., Pullman, J., Bottinger, E. P., Goldberg, I. J., & Susztak, K. (2015). Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nature Medicine, 21(1), 37-46. https://doi.org/10.1038/nm.3762