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. 2018 Jun 4;8:8539. doi: 10.1038/s41598-018-26804-8

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Integrated proteomic and metabolomic analysis 4 h and 24 h post IRI. (A) Metabolites and proteins altered during IRI were shortlisted based on their changed abundance in 4 h-IRI and 24 h-IRI compared to 4 h-C, 24 h-C and HC. A heat map using both metabolites (Italic font-style) and proteins (normal font-style) indicates a distinct pattern, in particular for FA β-oxidation and ketogenesis. (B) Proposed model of energy homeostasis 4 h and 24 h post IRI. Increased FFA metabolism was suggested according to increased FA transporters (CD36, Cpt1a), monoglyceride levels, FA β-oxidation enzymes (Acadsb, Echdc3), and ketogenesis. The metabolites derived from FA β-oxidation (acetyl-CoA) can directly feed into and sustain the TCA cycle. Metabolite generated from the TCA cycle (succinyl-CoA) and products from ketogenesis (acetoacetate) can subsequently form succinate catalysed by Succinyl-CoA:3-Ketoacid-CoA Transferase (Oxct1). Succinate is an essential substrate that can be fed directly into the electron transport chain (Complex II) and into the TCA cycle, maintaining and providing essential mitochondrial substrates. Accumulation of AMP and urea was observed in contralateral (uninjured) kidneys. Statistical analysis using a non-parametric Mann-Whitney test was used to assess significant changes in metabolite and protein abundances (Table S4).