Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development
Open accessAbstract
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.
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Pro-fibrotic macrophages commonly coordinate scar formation via interactions with fibroblasts, the major cellular source of pathological extracellular matrix deposition during fibrosis.
“pro-fibrotic macrophages commonly coordinate scar formation via a range of interactions with fibroblasts, the major cellular source of pathological extracellular matrix deposition during fibrosis18,27,74–78.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [74]
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- Authors
- 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.
- Affiliations
- University of Pennsylvania (US)
- University of California San Diego (US)
- Albert Einstein College of Medicine (US)
- NYU Langone Health (US)
- ORCID
- Venue
- Nature Medicine
- Published
- 2014-12-01
- Volume
- 21
- Issue
- 1
- Pages
- 37-46
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4444078
- OpenAlex
- W2050622384
- Cited by
- 1,555
- References
- 40
- Citations by year
- 2026: 165 · 2025: 186 · 2024: 219 · 2023: 172 · 2022: 182 · 2021: 173 · 2020: 151 · 2019: 91 · 2018: 72 · 2017: 73 · 2016: 46 · 2015: 23 · 2014: 1
- FWCI
- 37.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
- Funders
- University of Pennsylvania (P30DK19525)
- National Institutes of Health (1dp3dk094352-01, 094352, DK 020541, HL-73029, DK 19525, HL-45095)
- National Heart, Lung, and Blood Institute (R01HL045095, R01HL073029, R37HL045095)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 19525, DP3-DK-094352, R01DK087635, DK-076169, DK-020541, U24DK076169, P30 DK 19525, P60DK020541, R01DK076077, P30DK019525)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal and Vascular Pathologies
- Keywords
- renal fibrosis, tubulointerstitial fibrosis, fatty acid oxidation, renal tubular epithelial cells, lipid accumulation, chronic kidney disease, transcriptome, inflammation, energy metabolism, ATP depletion, dedifferentiation, fatty acid metabolism
- MeSH terms
- Animals, Epithelial Cells, Fatty Acids, Fibrosis, Gene Expression Regulation, Humans, Inflammation, Kidney Diseases, Kidney Tubules, Oxidation-Reduction, Signal Transduction, Gene Expression Profiling, Mice
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