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Conference/Presentation Title: | Protease activated-receptor-2 induced inflammation and fibrosis is mediated in part through activation of transforming growth factor-beta signalling. | Authors: | Gobe G.;Fairlie D.;Vesey D.;Owens E.;Iyer A.;Morais C.;Lohman R.;Suen J.;Johnson D.;Nikolic-Paterson D. | Monash Health Department(s): | Nephrology | Institution: | (Owens, Morais, Johnson, Gobe, Vesey) Centre for Kidney Disease Research, School of Medicine, Translational Research Institute, University of Queensland, Brisbane, Australia (Iyer, Lohman, Suen, Fairlie) Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia (Nikolic-Paterson) Department of Nephrology, Monash University, Monash Medical Centre, Clayton, Australia | Presentation/Conference Date: | 27-Sep-2016 | Copyright year: | 2016 | Publisher: | Blackwell Publishing | Publication information: | Nephrology. Conference: 15th Asian Pacific Congress of Nephrology, APCN and 52nd ANZSN ASM. Perth, WA Australia. 21 (Supplement 2) (pp 86), 2016. Date of Publication: September 2016. | Abstract: | Aim: To explore the pro-inflammatory and pro-fibrotic responses of primary human kidney tubular epithelial cells (HTECs) following activation of protease-activated receptor-2 (PAR-2) and/or the transforming growth factor-beta (TGF-beta) receptor. Background(s): Tubulointerstitial inflammation and fibrosis are observed in all progressive forms of chronic kidney disease (CKD) irrespective of the initiating insult. Recent evidence suggests that serine proteases, commonly produced following kidney injury, promote and exacerbate these responses by activating PAR-2 and TGF-beta receptors. Method(s): Confluent HTECs were treated with the synthetic PAR-2 agonist 2f-LIGRLO-NH2 (1 muM) and/or TGF-beta1 (5ng/ mL) in the presence or absence of the pan-protein kinase C (PKC) inhibitor Go6983, the TGF-beta receptor kinase inhibitor SB-431542, and PAR-2 antagonist GB88. Inductions of pro-inflammatory and pro-fibrotic molecules [e.g. CSF2, TNF-alpha, PAI- 1,MMP-1,MMP-9, and MMP-10] was measured at the mRNA and protein level by qPCR, western blot, and ELISA. Result(s): Alone, 2f-LIGRLO-NH2 significantly induced production range of molecules including CSF2, TNF-alpha, CTGF, PAI-1, MMP-1,MMP-9, and MMP-10 from HTEC. Smad2 was also activated by this treatment. TGF-beta1 treatment induced production CSF2, CTGF, and PAI-1 although to a lesser extent than with PAR-2 activation. Concurrent activation of PAR-2 and TGF-beta receptors gave a synergistic increase in the production of a number of these factors, particularly CSF2 and MMP-9. GB88, Go6983 and SB-431542 significantly reduced production of molecules CTGF, CSF2, PAI-1, and MMP-9. Conclusion(s): PAR-2 activation induces pro-inflammatory and pro-fibrotic responses in HTECs which involve PKC and TGF-beta signalling pathways. PAR-2 antagonists may be useful for pharmacotherapy of CKD, and are currently being tested for efficacy in animal models. | Conference Start Date: | 2016-09-17 | Conference End Date: | 2016-09-21 | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.1111/nep.12887 | ISSN: | 1320-5358 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/40313 | Type: | Conference Abstract | Subjects: | stromelysin 2 *transforming growth factor beta transforming growth factor beta receptor transforming growth factor beta1 tumor necrosis factor animal model agonist chronic kidney disease disease model enzyme linked immunosorbent assay epithelium cell *fibrosis *gene activation gene expression human *inflammation kidney injury Western blotting 4 [4 (1,3 benzodioxol 5 yl) 5 (2 pyridinyl) 1h imidazol 2 yl]benzamide endogenous compound granulocyte macrophage colony stimulating factor interstitial collagenase messenger RNA protein kinase C protein kinase C inhibitor *proteinase activated receptor 2 serine proteinase Smad2 protein enzyme linked immunosorbent assay disease model chronic kidney disease animal model agonist *fibrosis *gene activation gene expression human *inflammation kidney injury Western blotting epithelium cell |
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