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

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. Purinergic signalling in the kidney maintains homeostasis and mediates injury-induced inflammation. The extracellular conversion of ATP into adenosine is critical for modulating these processes. Here, the authors discuss the pathological conditions associated with extracellular ATP metabolism and novel strategies for their treatment. 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 disea