期刊
EBIOMEDICINE
卷 19, 期 -, 页码 73-83出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2017.04.011
关键词
Glucose; Purine; P2; Renal; Cytokine; CKD
资金
- BHF Immediate Postdoctoral Basic Science Research Fellow [FS/15/60/31510]
- MRC/Kidney Research UK Joint Clinical Training Fellowship [G0901956]
- Diamond Fund from Imperial College Healthcare Charity
- Mary Minton Chair of Renal Medicine
- National Institute for Health Research (NIHR) Biomedical Research Centre
- Imperial College Healthcare NHS Trust
- Imperial College London
- MRC [G0901956] Funding Source: UKRI
- British Heart Foundation [FS/15/60/31510] Funding Source: researchfish
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. (C) 2017 The Authors. Published by Elsevier B.V.
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