Hyun Mi Kang1, Seon Ho Ahn1,6, Peter Choi1, Yi-An Ko1, Seung Hyeok Han1, Frank Chinga1, Ae Seo Deok Park1, Jianling Tao1,6, Kumar Sharma2, James Pullman3, Erwin P Bottinger4, Ira J Goldberg5 & Katalin Susztak1,*
1Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 2Division of Nephrology, Department of Medicine, University of California, San Diego, Veterans Administration San Diego HealthCare System, La Jolla, California, USA. 3Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA. 4Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA. 5Department of Medicine, New York University Langone Medical Center, New York, New York, USA. 6Present addresses: Division of Nephrology, Department of Internal Medicine, Wonkwang University College of Medicine and Hospital, Jeonbuk, Republic of Korea (S.H.A.) and Division of Nephrology, Peking Union Medical College Hospital, Beijing, China (J.T.).
*Correspondence should be addressed to K.S.
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.