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Conversion of extracellular ATP into adenosine: a master switch in renal health and disease

  • Review Article
  • Published:

From Nature Reviews Nephrology

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Abstract

ATP and its ultimate degradation product adenosine are potent extracellular signalling molecules that elicit a variety of pathophysiological functions in the kidney through the activation of P2 and P1 purinergic receptors, respectively. Extracellular purines can modulate immune responses, balancing inflammatory processes and immunosuppression; indeed, alterations in extracellular nucleotide and adenosine signalling determine outcomes of inflammation and healing processes. The functional activities of ectonucleotidases such as CD39 and CD73, which hydrolyse pro-inflammatory ATP to generate immunosuppressive adenosine, are therefore pivotal in acute inflammation. Protracted inflammation may result in aberrant adenosinergic signalling, which serves to sustain inflammasome activation and worsen fibrotic reactions. Alterations in the expression of ectonucleotidases on various immune cells, such as regulatory T cells and macrophages, as well as components of the renal vasculature, control purinergic receptor-mediated effects on target tissues within the kidney. The role of CD39 as a rheostat that can have an impact on purinergic signalling in both acute and chronic inflammation is increasingly supported by the literature, as detailed in this Review. Better understanding of these purinergic processes and development of novel drugs targeting these pathways could lead to effective therapies for the management of acute and chronic kidney disease.

Key points

  • Extracellular ATP and/or ADP acting through P2 receptors exert profound effects on the immune system and also have an impact on kidney pathophysiology.

  • Extracellular adenosine is a signalling molecule in the kidney and in the immune system that acts through P1 or adenosine receptors, often opposing the effects of P2 receptor signalling.

  • The balance between extracellular ATP and adenosine concentrations is largely regulated by the activity of the CD39–CD73 axis and other ATP hydrolysing enzymes, such as the nucleotide pyrophosphatase/phosphodiesterase proteins.

  • CD39 and CD73, an ecto-5′-nucleotidase, constitute a key ‘extracellular master switch’ in the kidney in both health and disease.

  • CD39 plays a role in renal inflammation, immunomodulation, acute kidney injury, chronic kidney disease, diabetic nephropathy, polycystic kidney disease, transplantation and renal cell carcinoma.

  • Therapeutic options for kidney disease could include using currently available drugs or developing agents to target purinergic processing.

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Fig. 1: ATP–adenosine metabolic pathways within the kidney.
Fig. 2: CD39, ATP and adenosine in the activation of the NLRP3 inflammasome.
Fig. 3: CD39 and regulatory cell purinergic signalling modulates tissue injury and repair.
Fig. 4: Proposed effects of CD39 and adenosine in acute ischaemic kidney disease.
Fig. 5: CD4+CD25+/−CD39+ expression in the peripheral blood of patients with renal allograft rejection in transplantation rejection and states of tolerance.

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Acknowledgements

S.C.R. is funded by the Department of Defence grant W81XWH-16-1-0464 and also previously the National Institutes of Health grants R21-CA221702, R01-DK108894, R01-DK10372, 1R01-AI132389 and 5R01DK104714. B.K.K. has been supported by the US Department of Veterans Affairs Merit Review Program and also previously by the National Institutes of Health grants R01-DK061183 and R21-DK081041, and a pre-clinical research grant from AstraZeneca.

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Authors and Affiliations

  1. School of Medicine, Faculty of Health, Deakin University, Geelong, Victoria, Australia

    Karen M. Dwyer

  2. Departments of Internal Medicine, and Nutrition and Integrative Physiology, and Center on Aging, University of Utah Health Care System, Salt Lake City, UT, USA

    Bellamkonda K. Kishore

  3. Nephrology Research, VA Salt Lake City Health Care System, Salt Lake City, UT, USA

    Bellamkonda K. Kishore

  4. Division of Gastroenterology/Hepatology, Department of Medicine and Center for Inflammation Research, Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Simon C. Robson

Authors
  1. Karen M. Dwyer
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  2. Bellamkonda K. Kishore
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  3. Simon C. Robson
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Contributions

K.M.D., B.K.K. and S.C.R. all contributed to researching data for the article, writing the article and reviewing and editing the manuscript before submission. All authors substantially contributed to the discussion of the review contents.

Corresponding author

Correspondence to Karen M. Dwyer.

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Competing interests

K.M.D. has no conflicts to declare. S.C.R. has had grant support from Tizona for development and characterization of antibodies to CD39. B.K.K. received research grant support and collaborated with AstraZeneca, and has United States patents issued for the use of P2Y2 and P2Y12 antagonists for the treatment of nephrogenic diabetes insipidus and other diseases.

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Nature Reviews Nephrology thanks Gennady Yegutkin, Matthew Bailey and the other, anonymous, reviewer(s) for their contributions to the peer review of this work.

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Glossary

G proteins

A family of GTPase proteins involved in transmitting signals from extracellular stimuli to the cell interior.

Damage-associated molecular pattern

(DAMP). Molecules released from damaged or dying cells that trigger immune responses by interacting with pattern recognition receptors.

Purinome

All the proteins in a cell that utilize purine cofactors.

Treg-specific demethylated region

An evolutionarily conserved non-coding element within the FOXP3 gene locus that controls FOXP3 expression.

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Dwyer, K.M., Kishore, B.K. & Robson, S.C. Conversion of extracellular ATP into adenosine: a master switch in renal health and disease. Nat Rev Nephrol 16, 509–524 (2020). https://doi.org/10.1038/s41581-020-0304-7

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