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Immunometabolic rewiring of tubular epithelial cells in kidney disease

Abstract

Kidney tubular epithelial cells (TECs) have a crucial role in the damage and repair response to acute and chronic injury. To adequately respond to constant changes in the environment, TECs have considerable bioenergetic needs, which are supported by metabolic pathways. Although little is known about TEC metabolism, a number of ground-breaking studies have shown that defective glucose metabolism or fatty acid oxidation in the kidney has a key role in the response to kidney injury. Imbalanced use of these metabolic pathways can predispose TECs to apoptosis and dedifferentiation, and contribute to lipotoxicity and kidney injury. The accumulation of lipids and aberrant metabolic adaptations of TECs during kidney disease can also be driven by receptors of the innate immune system. Similar to their actions in innate immune cells, pattern recognition receptors regulate the metabolic rewiring of TECs, causing cellular dysfunction and lipid accumulation. TECs should therefore be considered a specialized cell type — like cells of the innate immune system — that is subject to regulation by immunometabolism. Targeting energy metabolism in TECs could represent a strategy for metabolically reprogramming the kidney and promoting kidney repair.

Key points

  • Kidney tubular epithelial cells (TECs) have a high energy demand, relying primarily on fatty acid oxidation as an energy source.

  • The metabolic and immune profile of TECs is affected by injury; further alterations occur with disease progression or repair processes.

  • Following exposure to cellular stress, TECs rewire their metabolism, resulting in an accumulation of lipids and lipotoxicity.

  • Activation of immunometabolic processes influence the response of TECs to stress; innate immune sensors act to sense immunological changes in the intracellular and extracellular environment but also regulate the metabolic needs, responses and phenotype of TECs.

  • Targeting (immuno)metabolism through, for example, the targeting of innate immune sensors and their metabolic responses may represent a novel strategy for treating or preventing kidney disease.

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Fig. 1: Energy and lipid synthesis pathways.
Fig. 2: Metabolic changes in TECs in response to AKI and CKD.
Fig. 3: The relationship between tubular metabolism and cellular phenotype.
Fig. 4: Immunometabolic pathways in TECs.

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All authors contributed substantially to discussion of the content, writing of the article, and reviewing and/or editing of the manuscript before submission.

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Correspondence to Sandrine Florquin or Alessandra Tammaro.

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Glossary

Lipids

A ubiquitous group of compounds that are insoluble in water and essential for energy metabolism, cell membrane integrity, cell signalling and general homeostasis.

Complex lipids

Unlike simple lipids, which contain a maximum of two types of chemical moieties (e.g. fatty acids and glycerol), complex lipids contain three or more chemical moieties (e.g. fatty acids, glycerol and a phosphate group).

Long-chain fatty acids

Fatty acids containing more than 12 carbon atoms and are an important energy source in the kidney.

Pathogen-associated molecular patterns

(PAMPs). Molecules that are released upon pathogen infection and activate the pattern recognition receptors of the innate immune response.

Damage-associated molecular patterns

(DAMPs). Molecules that are released upon damage and activate the pattern recognition receptors of the innate immune response.

Trained immunity

The concept that, like the adaptive immune system, the innate immune response can also have an immune memory.

Lipotoxicity

The accumulation of lipids in tissues that is harmful for the function and structure of the cells. For instance, it can reduce energy metabolism.

Perilipin 2

A protein that is important for lipid droplet metabolism and is involved in the storage of lipids.

Mitochondrial antiviral-signalling proteins

Proteins that are located in the inner membrane of the mitochondria, peroxisomes and endoplasmic reticulum that are essential for the antiviral innate immune response.

Translation–elongation factors

Proteins that have important roles during protein synthesis, especially in the elongation cycle at the ribosome.

Dynamin-1-like protein

A protein involved in mitochondrial fission, which is important for mitochondrial function.

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van der Rijt, S., Leemans, J.C., Florquin, S. et al. Immunometabolic rewiring of tubular epithelial cells in kidney disease. Nat Rev Nephrol 18, 588–603 (2022). https://doi.org/10.1038/s41581-022-00592-x

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