title: Role of Protease-Activated Receptor 2 in Regulating Focal Segmental Glomerulosclerosis.
abstract: Background /Aims: The underlying mechanisms leading to focal segmental glomerulosclerosis (FSGS) are lacking. In this report, we examined the role of protease-activated receptors (PARs) subtype PAR2 and its downstream signals in regulating the pathophysiological process of FSGS.
  
  
  METHODS
  Nephropathy was induced by intravenous injections of adriamycin (ADR) in rats to study FSGS. Western Blot analysis and ELISA were employed to determine the protein expression levels of PAR2 and its downstream signal pathways as well as the levels of PICs.
  
  
  RESULTS
  In ADR rats, expression of PAR2, PKCε and PKA was amplified and this was accompanied with increases of pro-inflammatory cytokines (PICs) including IL-1β, IL-6 and TNF-α. Inhibition of PAR2 signal by systemic administration of FSLLRY-NH2 (FSL) attenuated amplification of PICs. Notably, FSL further influenced key molecular mediators during development of FSGS. i.e., it specifically restored the impaired nephrin and attenuated the exaggerated transforming growth factor beta 1 (TGF-β1), caspase-9 and desmin thereby improving worsened renal functions and glomerular injury. Consistent with this, in cultured podocytes FSL also largely restored downregulation of nephrin and attenuated amplifications of caspase-9 and desmin induced by TGF-β1.
  
  
  CONCLUSIONS
  Results of this study suggest that PAR2 plays an important role in mediating renal injury induced by glomerulosclerosis. Inhibition of PAR2 signal pathway has a protective effect on FSGS mainly via PIC and TGF-β1 mechanisms. Targeting one or more of these signaling molecules may present new opportunities for treatment and management of FSGS observed in patients.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.forename: Yanfa
authors.initials: Y
authors.lastname: He
authors.forename: Mingzheng
authors.initials: M
authors.lastname: Wang
authors.forename: Pei
authors.initials: P
authors.lastname: Lv
authors.forename: Jianzhen
authors.initials: J
authors.lastname: Liu
authors.forename: Junxia
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D003893:Desmin / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin; D005786:Gene Expression Regulation; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology*; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D003893:Desmin; C508716:H-Phe-Ser-Leu-Leu-Arg-Tyr-NH2; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D015850:Interleukin-6; D008565:Membrane Proteins; D009842:Oligopeptides; D044464:Receptor, PAR-2; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C113267:nephrin; D004317:Doxorubicin; D017868:Cyclic AMP-Dependent Protein Kinases; D051744:Protein Kinase C-epsilon; C506435:Casp9 protein, rat; D053453:Caspase 9
keywords: PAR2; Pro-inflammatory cytokines; Renal fibrosis; TGF-β1