Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development
| Autor: | Katalin Susztak, Ira J. Goldberg, Seung Hyeok Han, Erwin P. Bottinger, Hyun Mi Kang, James Pullman, Yi-An Ko, Jianling Tao, Peter S. Choi, Seon Ho Ahn, Kumar Sharma, Ae Seo Deok Park, Frank Chinga |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Biology General Biochemistry Genetics and Molecular Biology Transcriptome Mice chemistry.chemical_compound Fibrosis Internal medicine medicine Renal fibrosis Animals Humans Beta oxidation Inflammation Fatty acid metabolism Gene Expression Profiling Fatty Acids Epithelial Cells General Medicine medicine.disease Kidney Tubules Endocrinology Gene Expression Regulation chemistry Tubulointerstitial fibrosis Kidney Diseases Oxidation-Reduction Intracellular Signal Transduction Kidney disease |
| Zdroj: | Nature Medicine. 21:37-46 |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/nm.3762 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|