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Nonesterified free fatty acids enhance the inflammatory response in renal tubules by inducing extracellular ATP release

Sun, H; Sun, Z; Varghese, Z; Guo, Y; Moorhead, JF; Unwin, RJ; Ruan, XZ; (2020) Nonesterified free fatty acids enhance the inflammatory response in renal tubules by inducing extracellular ATP release. American Journal of Physiology. Renal Physiology , 319 (2) F292-F303. 10.1152/ajprenal.00098.2020. Green open access

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Abstract

In proteinuric renal diseases, excessive plasma nonesterified free fatty acids bound to albumin can leak across damaged glomeruli to be reabsorbed by renal proximal tubular cells and cause inflammatory tubular cells damage by as yet unknown mechanisms. The present study was designed to investigate these mechanisms induced by palmitic acid (PA; one of the nonesterified free fatty acids) overload. Our results show that excess PA stimulates ATP release through the pannexin 1 channel in human renal tubule epithelial cells (HK-2), increasing extracellular ATP concentration approximately threefold compared with control. The ATP release is dependent on caspase-3/7 activation induced by mitochondrial reactive oxygen species. Furthermore, extracellular ATP aggravates PA-induced monocyte chemoattractant protein-1 secretion and monocyte infiltration of tubular cells, enlarging the inflammatory response in both macrophages and HK-2 cells via the purinergic P2X7 receptor-mammalian target of rapamycin-forkhead box O1-thioredoxin-interacting protein/NOD-like receptor protein 3 inflammasome pathway. Hence, PA increases mitochondrial reactive oxygen species-induced ATP release and inflammatory stress, which cause a “first hit,” while ATP itself is a “second hit” in amplifying the renal tubular inflammatory response. Thus, inhibition of ATP release or the purinergic P2X7 receptor may be an approach to reduce renal inflammation and improve renal function.

Type: Article
Title: Nonesterified free fatty acids enhance the inflammatory response in renal tubules by inducing extracellular ATP release
Open access status: An open access version is available from UCL Discovery
DOI: 10.1152/ajprenal.00098.2020
Publisher version: https://doi.org/10.1152/ajprenal.00098.2020
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: nonesterified free fatty acids, purinergic-P2X7 receptor-mammalian target of rapamycin-forkhead box O1-thioredoxin-interacting protein/NOD-like receptor protein 3, renal tubular inflammation
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/10115128
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