title: Expression of gremlin, a bone morphogenetic protein antagonist, in glomerular crescents of pauci-immune glomerulonephritis.
abstract: BACKGROUND
  Recent evidence in vitro and in vivo suggests that gremlin, a bone morphogenetic protein antagonist, is participating in tubular epithelial mesenchymal transition (EMT) in diabetic nephropathy as a downstream mediator of TGF-beta. Since EMT also occurs in parietal epithelial glomerular cells (PECs) leading to crescent formation, we hypothesized that gremlin could participate in this process. With this aim we studied its expression in 30 renal biopsies of patients with pauci-immune crescentic nephritis.
  
  
  METHODS
  Gremlin was detected by in situ hybridization (ISH) and immunohistochemistry (IMH) and TGF-beta by ISH and Smads by southwestern histochemistry (SWH). Phosphorylated Smad2, CTGF, BMP-7, PCNA, alpha-SMA, synaptopodin, CD-68, and phenotypic markers of PECs (cytokeratin, E-cadherin), were detected by IMH. In cultured human monocytes, gremlin and CTGF induction by TGF-beta was studied by western blot.
  
  
  RESULTS
  We observed strong expression of gremlin mRNA and protein in cellular and fibrocellular crescents corresponding to proliferating PECs and monocytes, in co-localization with TGF-beta. A marked over-expression of gremlin was also observed in tubular and infiltrating interstitial cells, correlating with tubulointerstitial fibrosis (r=0.59; P<0.01). A nuclear Smad activation in the same tubular cells, that are expressing TGF-beta and gremlin, was detected. In human cultured monocytes, TGF-beta induced gremlin production while CTGF expression was not detected.
  
  
  CONCLUSIONS
  We postulate that gremlin may play a role in the fibrous process in crescentic nephritis, both in glomerular crescentic and tubular epithelial cells. The co-localization of gremlin and TGF-beta expression found in glomeruli and tubular cells suggest that gremlin may be important in mediating some of the pathological effects of TGF-beta.
authors.affiliation: Division Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile. smezzano@uach.cl
authors.forename: Sergio
authors.initials: S
authors.lastname: Mezzano
authors.forename: Alejandra
authors.initials: A
authors.lastname: Droguett
authors.forename: M Eugenia
authors.initials: ME
authors.lastname: Burgos
authors.forename: Claudio
authors.initials: C
authors.lastname: Aros
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Ardiles
authors.forename: Claudio
authors.initials: C
authors.lastname: Flores
authors.forename: Daniel
authors.initials: D
authors.lastname: Carpio
authors.forename: Gisselle
authors.initials: G
authors.lastname: Carvajal
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
mesh_terms: D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005355:Fibrosis; D005921:Glomerulonephritis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology
chemical_list: D019485:Bone Morphogenetic Proteins; C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta