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Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development

Nature Medicine volume 21, pages 37–46 (2015)Cite this article

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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.

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Figure 1: The transcriptional landscape of human TIF.
Figure 2: Dysregulation of FAO in mouse models of TIF.
Figure 3: Role of TEC lipid accumulation in tubular interstitial fibrosis development.
Figure 4: TGFB1 suppresses FAO in renal TECs.
Figure 5: TGFB1 suppresses FAO in a SMAD3- and PPARGC1A-dependent manner.
Figure 6: Genetic or pharmacological restoration of FAO protects animals from fibrosis development.

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Acknowledgements

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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Author notes

  1. Seon Ho Ahn & Jianling Tao

    Present address: Present 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.).,

Authors and Affiliations

  1. Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Hyun Mi Kang, Seon Ho Ahn, Peter Choi, Yi-An Ko, Seung Hyeok Han, Frank Chinga, Ae Seo Deok Park, Jianling Tao & Katalin Susztak

  2. Division of Nephrology, Department of Medicine, University of California, San Diego, Veterans Administration San Diego HealthCare System, La Jolla, California, USA

    Kumar Sharma

  3. Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA

    James Pullman

  4. Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA

    Erwin P Bottinger

  5. Department of Medicine, New York University Langone Medical Center, New York, New York, USA

    Ira J Goldberg

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Contributions

H.M.K. performed all in vitro and most in vivo experiments. S.H.A. and K. Susztak generated and analyzed the CD36 transgenic animals. S.H.H., F.C. and J.T. helped with the animal experiments. P.C., A.S.D.P. and J.P. were involved in collecting and analyzing human kidney tissue samples. Y.-A.K. generated and analyzed the ChIP-Seq data. E.P.B., K. Sharma and I.J.G. provided help with conceptual design. H.M.K. and K. Susztak wrote the paper, and I.J.G. assisted with editing the manuscript.

Corresponding author

Correspondence to Katalin Susztak.

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Competing interests

The laboratory of K. Susztak received research support from Boehringer Ingelheim.

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Kang, H., Ahn, S., Choi, P. et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med 21, 37–46 (2015). https://doi.org/10.1038/nm.3762

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