PAR2 activation on human tubular epithelial cells engages converging signaling pathways to induce an inflammatory and fibrotic milieu.

Autor:	Vesey DA; Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland at the Princess Alexandra Hospital, Brisbane, QLD, Australia.; Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, QLD, Australia., Iyer A; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.; Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia., Owen E; Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland at the Princess Alexandra Hospital, Brisbane, QLD, Australia., Kamato D; Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia., Johnson DW; Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland at the Princess Alexandra Hospital, Brisbane, QLD, Australia.; Department of Kidney and Transplant Services, Princess Alexandra Hospital, Brisbane, QLD, Australia., Gobe GC; Centre for Kidney Disease Research, Translational Research Institute, The University of Queensland at the Princess Alexandra Hospital, Brisbane, QLD, Australia.; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia., Fairlie DP; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.; Centre for Inflammation and Disease Research, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia., Nikolic-Paterson DJ; Department of Nephrology, Monash Health and Monash University Centre for Inflammatory Diseases, Monash Medical Centre, Clayton, VIC, Australia.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2024 Jun 28; Vol. 15, pp. 1382094. Date of Electronic Publication: 2024 Jun 28 (Print Publication: 2024).
DOI:	10.3389/fphar.2024.1382094
Abstrakt:	Key features of chronic kidney disease (CKD) include tubulointerstitial inflammation and fibrosis. Protease activated receptor-2 (PAR2), a G-protein coupled receptor (GPCR) expressed by the kidney proximal tubular cells, induces potent proinflammatory responses in these cells. The hypothesis tested here was that PAR2 signalling can contribute to both inflammation and fibrosis in the kidney by transactivating known disease associated pathways. Using a primary cell culture model of human kidney tubular epithelial cells (HTEC), PAR2 activation induced a concentration dependent, PAR2 antagonist sensitive, secretion of TNF, CSF2, MMP-9, PAI-1 and CTGF. Transcription factors activated by the PAR2 agonist 2F, including NFκB, AP1 and Smad2, were critical for production of these cytokines. A TGF-β receptor-1 (TGF-βRI) kinase inhibitor, SB431542, and an EGFR kinase inhibitor, AG1478, ameliorated 2F induced secretion of TNF, CSF2, MMP-9, and PAI-1. Whilst an EGFR blocking antibody, cetuximab, blocked PAR2 induced EGFR and ERK phosphorylation, a TGF-βRII blocking antibody failed to influence PAR2 induced secretion of PAI-1. Notably simultaneous activation of TGF-βRII (TGF-β1) and PAR2 (2F) synergistically enhanced secretion of TNF (2.2-fold), CSF2 (4.4-fold), MMP-9 (15-fold), and PAI-1 (2.5-fold). In summary PAR2 activates critical inflammatory and fibrotic signalling pathways in human kidney tubular epithelial cells. Biased antagonists of PAR2 should be explored as a potential therapy for CKD. Competing Interests: DJ has received consultancy fees, research grants, speaker’s honoraria and travel sponsorships from Baxter Healthcare and Fresenius Medical Care, consultancy fees from Astra Zeneca and AWAK, speaker’s honoraria and travel sponsorships from ONO, and travel sponsorships from Amgen. He is a current recipient of an Australian National Health and Medical Research Council Practitioner Fellowship. DF is an inventor on a patent AU20109033378 covering PAR2 agonists and antagonists that is owned by The University of Queensland. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Vesey, Iyer, Owen, Kamato, Johnson, Gobe, Fairlie and Nikolic-Paterson.)
Databáze:	MEDLINE
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