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Metabolic reprogramming and tolerance during sepsis-induced AKI

Nature Reviews Nephrology volume 13, pages 143–151 (2017)Cite this article

Subjects

Key Points

  • Resistance and tolerance mechanisms govern the infection response and determine host survival

  • A switch to Warburg metabolism seems to be an important survival strategy in immune cells and possibly in tubular epithelial cells in response to inflammation

  • Reprogramming of metabolic pathways is a key cellular strategy to execute resistance and tolerance protective programmes

  • Early metabolic reprogramming in the response to inflammation is crucial to determine the acute response of the cell, to avoid cell death and to determine the repair phenotype during recovery

  • Understanding of resistance and tolerance mechanisms in sepsis might provide a basis for the development of therapeutic strategies to prevent or reverse organ damage, promote recovery and decrease mortality

Abstract

The host defence against infection is an adaptive response in which several mechanisms are deployed to decrease the pathogen load, limit tissue injury and restore homeostasis. In the past few years new evidence has suggested that the ability of the immune system to limit the microbial burden — termed resistance — might not be the only defence mechanism. In fact, the capacity of the host to decrease its own susceptibility to inflammation- induced tissue damage — termed tolerance — might be as important as resistance in determining the outcome of the infection. Metabolic adaptations are central to the function of the cellular immune response. Coordinated reprogramming of metabolic signalling enables cells to execute resistance and tolerance pathways, withstand injury, steer tissue repair and promote organ recovery. During sepsis-induced acute kidney injury, early reprogramming of metabolism can determine the extent of organ dysfunction, progression to fibrosis, and the development of chronic kidney disease. Here we discuss the mechanisms of tolerance that act in the kidney during sepsis, with particular attention to the role of metabolic responses in coordinating these adaptive strategies. We suggest a novel conceptual model of the cellular and organic response to sepsis that might lead to new avenues for targeted, organ-protective therapies.

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Figure 1: The relationship between health fitness and pathogen load.
Figure 2: Putative pathways that regulate the metabolic response of naive macrophages to sepsis.
Figure 3: Model of metabolic reprogramming in tubular epithelial cells during sepsis.
Figure 4: Potential strategies for the assessment of renal tolerance in patients with sepsis.

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Acknowledgements

H.G. is supported by NIH grants 1K12HL109068-02 and 1K08GM117310-01A1.

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Authors and Affiliations

  1. Department of Critical Care Medicine, Center for Critical Care Nephrology, University of Pittsburgh, School of Medicine, Room 604 Scaife Hall, 3550 Terrace Street, Pittsburgh, 15261, Pennsylvania, USA

    Hernando Gómez & John A. Kellum

  2. Department of Nephrology, Dialysis and Transplantation, San Bortolo Hospital, International Renal Research Institute of Vicenza, Viale Rodolfi 37, Vicenza, 36100, Italy

    Claudio Ronco

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All authors researched the data, discussed the content, wrote the article and reviewed or edited the manuscript before submission.

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J.A.K. has received consulting fees and grant support from Astute Medical. H.G. and C.R. declare no competing interests.

PowerPoint slides

Glossary

Warburg effect

A coordinated change in cellular metabolism from oxidative phosphorylation to glycolysis to support the production of ATP and essential structural components required by the cell. This switch in metabolism can occur even in aerobic conditions.

Autophagy

An intracellular degradation pathway in which cellular components are taken up by autophagosomes and transported to lysosomes for degradation and recycling.

Oxidative phosphorylation

A metabolic process in which electrons derived from oxidation of carbon fuels (such as glucose and fats) are transported through electron acceptors and donors in the inner mitochondrial membrane. This process releases the energy required to generate adenosine triphosphate in the presence of oxygen.

Tricarboxylic acid cycle

A series of enzyme-catalysed reactions that through oxidation of acetyl-coenzyme A (derived from carbohydrate, fat and protein), yields reducing equivalents such as NADH, which are necessary for many processes including ATP generation.

Mitophagy

A specialized form of autophagy that targets and degrades dysfunctional mitochondria.

Biogenesis

Mitochondrial biogenesis is a coordinated process that involves both nuclear and mitochondrial DNA and results in the regeneration of new mitochondria.

Epithelial-to-mesenchymal transition

In the context of organ injury, epithelial-to-mesenchymal transition refers to the process by which epithelial cells undergo a transition to myofibroblasts, which produce collagenous matrix and promote tissue fibrosis.

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Gómez, H., Kellum, J. & Ronco, C. Metabolic reprogramming and tolerance during sepsis-induced AKI. Nat Rev Nephrol 13, 143–151 (2017). https://doi.org/10.1038/nrneph.2016.186

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