P2X4 receptor exacerbates ischemic AKI and induces renal proximal tubular NLRP3 inflammasome signaling.

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ID: 98234
2020
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Abstract
We tested the hypothesis that the P2X4 purinergic receptor (P2X4) exacerbates ischemic acute kidney injury (AKI) by promoting renal tubular inflammation after ischemia and reperfusion (IR). Supporting this, P2X4-deficient (KO) mice were protected against ischemic AKI with significantly attenuated renal tubular necrosis, inflammation, and apoptosis when compared to P2X4 wild-type (WT) mice subjected to renal IR. Furthermore, WT mice treated with P2X4 allosteric agonist ivermectin had exacerbated renal IR injury whereas P2X4 WT mice treated with a selective P2X4 antagonist (5-BDBD) were protected against ischemic AKI. Mechanistically, induction of kidney NLRP3 inflammasome signaling after renal IR was significantly attenuated in P2X4 KO mice. A P2 agonist ATPγS increased NLRP3 inflammasome signaling (NLRP3 and caspase 1 induction and IL-1β processing) in isolated renal proximal tubule cells from WT mice whereas these increases were absent in renal proximal tubules isolated from P2X4 KO mice. Moreover, 5-BDBD attenuated ATPγS induced NLRP3 inflammasome induction in renal proximal tubules from WT mice. Finally, P2X4 agonist ivermectin induced NLRP3 inflammasome and pro-inflammatory cytokines in cultured human proximal tubule cells. Taken together, our studies suggest that renal proximal tubular P2X4 activation exacerbates ischemic AKI and promotes NLRP3 inflammasome signaling.
Reference Key
han2020p2x4faseb Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Han, Sang Jun;Lovaszi, Marianna;Kim, Mihwa;D'Agati, Vivette;Haskó, György;Lee, H Thomas;
Journal faseb journal : official publication of the federation of american societies for experimental biology
Year 2020
DOI
10.1096/fj.201903287R
URL
Keywords
inflammation apoptosis inflammasome necrosis ischemia and reperfusion injury neutrophil

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