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Targeting immune cell metabolism in kidney diseases

Abstract

Insights into the relationship between immunometabolism and inflammation have enabled the targeting of several immunity-mediated inflammatory processes that underlie infectious diseases and cancer or drive transplant rejection, but this field remains largely unexplored in kidney diseases. The kidneys comprise heterogeneous cell populations, contain distinct microenvironments such as areas of hypoxia and hypersalinity, and are responsible for a functional triad of filtration, reabsorption and secretion. These distinctive features create myriad potential metabolic therapeutic targets in the kidney. Immune cells have crucial roles in the maintenance of kidney homeostasis and in the response to kidney injury, and their function is intricately connected to their metabolic properties. Changes in nutrient availability and biomolecules, such as cytokines, growth factors and hormones, initiate cellular signalling events that involve energy-sensing molecules and other metabolism-related proteins to coordinate immune cell differentiation, activation and function. Disruption of homeostasis promptly triggers the metabolic reorganization of kidney immune and non-immune cells, which can promote inflammation and tissue damage. The metabolic differences between kidney and immune cells offer an opportunity to specifically target immunometabolism in the kidney.

Key points

  • The unique kidney anatomy and physiology might enable the targeting of immunometabolism as a new therapeutic strategy to treat immunity-driven kidney diseases.

  • Immune and kidney parenchymal cells respond to a variety of stimuli by reprogramming their metabolism, which coordinates their effector functions.

  • Targeting metabolic pathways and energy-sensing molecules has potential to prevent or ameliorate acute kidney injury and chronic kidney disease.

  • Metabolic reprogramming of immune cells towards an anti-inflammatory profile might prevent the establishment of chronic inflammation and contribute to organ preservation after kidney injury.

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Fig. 1: Main pathways of cellular metabolism.
Fig. 2: Macrophage and dendritic cell metabolism.
Fig. 3: Potential metabolic pathways of immune cells involved in AKI and CKD.
Fig. 4: Targeting immunometabolism to treat kidney diseases.

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Acknowledgements

The authors are extremely thankful to A. Stacy at the National Institute of Allergy and Infectious Diseases, National Institute of Health (NAID/NIH) for carefully reading the manuscript before submission. This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2015/26682-6; 2017/02564-7; 2019/14755-0), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), financial code 001, CAPES COFECUB and The PEW Latin American fellowship from the Pew Charitable Trusts (VA-O). The authors apologize to all colleagues whose work could not be cited owing to space restrictions.

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Correspondence to Niels Olsen Saraiva Câmara.

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Glossary

Immunosenescence

Ageing-associated changes in the immune system.

Contraction phase

A phase of inflammatory response whereby homeostasis is restored, and effector immune cells die or become memory cells.

Anaplerotic reactions

Metabolic reactions aimed at replenishing tricarboxylic acid cycle intermediates.

Lactylation

Post-translational modification characterized by the addition of a lactyl group to a histone.

Ferroptotic cell death

An iron-dependent form of cell death.

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Basso, P.J., Andrade-Oliveira, V. & Câmara, N.O.S. Targeting immune cell metabolism in kidney diseases. Nat Rev Nephrol 17, 465–480 (2021). https://doi.org/10.1038/s41581-021-00413-7

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