title: Purinergic signaling in kidney disease.
abstract: Nucleotides are key subunits for nucleic acids and provide energy for intracellular metabolism. They can also be released from cells to act physiologically as extracellular messengers or pathologically as danger signals. Extracellular nucleotides stimulate membrane receptors in the P2 and P1 family. P2X are ATP-activated cation channels; P2Y and P1 are G-protein coupled receptors activated by ATP, ADP, UTP, and UDP in the case of P2 or adenosine for P1. Renal P2 receptors influence both vascular contractility and tubular function. Renal cells also express ectonucleotidases that rapidly hydrolyze extracellular nucleotides. These enzymes integrate this multireceptor purinergic-signaling complex by determining the nucleotide milieu to titrate receptor activation. Purinergic signaling also regulates immune cell function by modulating the synthesis and release of various cytokines such as IL1-β and IL-18 as part of inflammasome activation. Abnormal or excessive stimulation of this intricate paracrine system can be pro- or anti-inflammatory, and is also linked to necrosis and apoptosis. Kidney tissue injury causes a localized increase in ATP concentration, and sustained activation of P2 receptors can lead to renal glomerular, tubular, and vascular cell damage. Purinergic receptors also regulate the activity and proliferation of fibroblasts, promoting both inflammation and fibrosis in chronic disease. In this short review we summarize some of the recent findings related to purinergic signaling in the kidney. We focus predominantly on the P2X7 receptor, discussing why antagonists have so far disappointed in clinical trials and how advances in our understanding of purinergic signaling might help to reposition these compounds as potential treatments for renal disease.
authors: British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, Scotland, UK.
authors: Robert I
authors: RI
authors: Menzies
authors: Imperial College Renal and Transplant Centre, Department of Medicine, Imperial College London, UK.
authors: Frederick W
authors: FW
authors: Tam
authors: Cardiovascular and Metabolic Diseases Biotech Unit, AstraZeneca Gothenburg, Sweden; UCL Centre for Nephrology, University College London, London, UK. Electronic address: robert.unwin@ucl.ac.uk.
authors: Robert J
authors: RJ
authors: Unwin
authors: British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, Scotland, UK.
authors: Matthew A
authors: MA
authors: Bailey
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008024:Ligands; D011685:Purine Nucleotides / Q000378:metabolism*; D058920:Purinergic P2X Receptor Antagonists / Q000627:therapeutic use; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000187:drug effects / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7 / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008024:Ligands; C546468:P2RX7 protein, human; D011685:Purine Nucleotides; D058920:Purinergic P2X Receptor Antagonists; D018047:Receptors, Purinergic P1; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000241:Adenosine
keywords: ATP; P2X; P2Y; adenosine; inflammation; kidney; renal tubule; vasculature