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.
Bibliographical noteFunding Information:
Financial support for this work was provided by the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK087635 and R01DK076077 to K. Susztak) and the Diabetic Complications Consortium (DiaComp, http://www.diacomp.org; grant DK076169 to K. Susztak and E.P.B.). I.J.G. is supported by US National Institutes of Health grants HL45095 and HL73029. K. Sharma is supported by US National Institutes of Health grant DP3 DK 094352. H.M.K. is supported by a post-doctoral fellowship from the Juvenile Diabetes Research Foundation (3-2013-182). We thank D. Melton (Harvard Medical School) for providing TRE-ICNotch1 animals. We thank the Einstein (P60-DK020541) and Penn Diabetes Research Centers (P30-DK19525) for GC-FID and Seahorse measurements, respectively, and the Einstein Analytical imaging facility for the electron microscopy studies. Part of this work was presented at the Annual Nephrology Society Meetings in 2011 and 2013.
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All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)