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Hyperglycemia-induced renal P2X7 receptor activation enhances diabetes-related injury

Menzies, RI; Booth, JWR; Mullins, JJ; Bailey, MA; Tam, FWK; Norman, JT; Unwin, RJ; (2017) Hyperglycemia-induced renal P2X7 receptor activation enhances diabetes-related injury. EBioMedicine , 19 pp. 73-83. 10.1016/j.ebiom.2017.04.011. Green open access

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Abstract

Diabetes is a leading cause of renal disease. Glomerular mesangial expansion and fibrosis are hallmarks of diabetic nephropathy and this is thought to be promoted by infiltration of circulating macrophages. Monocyte chemoattractant protein-1 (MCP-1) has been shown to attract macrophages in kidney diseases. P2X7 receptors (P2X7R) are highly expressed on macrophages and are essential components of pro-inflammatory signaling in multiple tissues. Here we show that in diabetic patients, renal P2X7R expression is associated with severe mesangial expansion, impaired glomerular filtration (≤ 40 ml/min/1.73 sq. m.), and increased interstitial fibrosis. P2X7R activation enhanced the release of MCP-1 in human mesangial cells cultured under high glucose conditions. In mice, P2X7R-deficiency prevented glomerular macrophage attraction and collagen IV deposition; however, the more severe interstitial inflammation and fibrosis often seen in human diabetic kidney diseases was not modelled. Finally, we demonstrate that a P2X7R inhibitor (AZ11657312) can reduce renal macrophage accrual following the establishment of hyperglycemia in a model of diabetic nephropathy. Collectively these data suggest that P2X7R activation may contribute to the high prevalence of kidney disease found in diabetics.

Type: Article
Title: Hyperglycemia-induced renal P2X7 receptor activation enhances diabetes-related injury
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ebiom.2017.04.011
Publisher version: https://doi.org/10.1016/j.ebiom.2017.04.011
Language: English
Additional information: © 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Glucose; Purine; P2; Renal; Cytokine; CKD
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Renal Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1551578
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