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 M. Pullman, Erwin P. Bottinger, Ira J. Goldberg, Katalin Susztak

Research output: Contribution to journalArticle

248 Citations (Scopus)

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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Fibrosis
Fatty Acids
Epithelial Cells
Kidney
Oxidation
Metabolism
Cell Dedifferentiation
Kidney Tubules
Lipids
Kidney Diseases
Cell death
Chronic Renal Insufficiency
Transcriptome
Chronic Kidney Failure
Cell Death
Genes
Adenosine Triphosphate
Genome
Pharmacology
Inflammation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Kang, H. M., Ahn, S. H., Choi, P., Ko, Y. A., Han, S. H., Chinga, F., ... 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

Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. / Kang, Hyun Mi; Ahn, Seon Ho; Choi, Peter; Ko, Yi An; Han, Seung Hyeok; Chinga, Frank; Park, Ae Seo Deok; Tao, Jianling; Sharma, Kumar; Pullman, James M.; Bottinger, Erwin P.; Goldberg, Ira J.; Susztak, Katalin.

In: Nature Medicine, Vol. 21, No. 1, 01.01.2015, p. 37-46.

Research output: Contribution to journalArticle

Kang, HM, Ahn, SH, Choi, P, Ko, YA, Han, SH, Chinga, F, Park, ASD, Tao, J, Sharma, K, Pullman, JM, Bottinger, EP, Goldberg, IJ & Susztak, K 2015, 'Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development', Nature Medicine, vol. 21, no. 1, pp. 37-46. https://doi.org/10.1038/nm.3762
Kang, Hyun Mi ; Ahn, Seon Ho ; Choi, Peter ; Ko, Yi An ; Han, Seung Hyeok ; Chinga, Frank ; Park, Ae Seo Deok ; Tao, Jianling ; Sharma, Kumar ; Pullman, James M. ; Bottinger, Erwin P. ; Goldberg, Ira J. ; Susztak, Katalin. / Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. In: Nature Medicine. 2015 ; Vol. 21, No. 1. pp. 37-46.
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