title: γ-Secretase inhibition promotes fibrotic effects of albumin in proximal tubular epithelial cells.
abstract: OBJECTIVE
  Albuminuria is an important biomarker of renal dysfunction and is a major mediator of renal damage and fibrosis during kidney disease. The mechanisms underlying albumin-induced renal fibrosis remain unclear. There has been significant interest in γ-secretase activity in tubular epithelial cells in recent times; however, its potential role in albumin-induced fibrosis has not been investigated.
  
  
  METHODS
  The primary aim of this study was to examine the role of γ-secretase in albumin-induced fibrotic effects in proximal tubular cells. The effects of increasing albumin concentrations on fibrosis indicators and mediators in the human HK-2 cell line were examined in the presence and absence of a γ-secretase inhibitor, compound E.
  
  
  RESULTS
  Treatment with albumin resulted in a number of pro-fibrotic effects, including up-regulation of fibronectin, TGF-β1 and the EGF-R. Interestingly, similar effects were observed in response to treatment with the γ-secretase inhibitor, compound E. Co-treatment of cells with albumin and an EGF-R inhibitor, AG-1478, resulted in significant inhibition of the observed pro-fibrotic effects, suggesting a major role for the EGF-R in albumin-induced fibrotic events. Albumin-induced effects on the EGF-R appeared to be mediated through inhibition of γ-secretase activity and were dependent on ERK-MAPK signalling.
  
  
  CONCLUSIONS
  These results provide novel insights into the mechanisms of albumin-induced fibrotic effects in tubular epithelial cells, suggesting important roles for the γ-secretase and the EGF-R. These results suggest that the proposed use of γ-secretase inhibitors as anti-fibrotic agents requires further investigation.
authors.affiliation: UCD School of Biomolecular and Biomedical Sciences, UCD Conway Institute, University College Dublin, Belfield, Ireland.
authors.forename: C
authors.initials: C
authors.lastname: Slattery
authors.forename: Y
authors.initials: Y
authors.lastname: Jang
authors.forename: W A
authors.initials: WA
authors.lastname: Kruger
authors.forename: D H
authors.initials: DH
authors.lastname: Hryciw
authors.forename: A
authors.initials: A
authors.lastname: Lee
authors.forename: P
authors.initials: P
authors.lastname: Poronnik
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology; D002417:Cattle; D002460:Cell Line; D016895:Culture Media, Serum-Free; D004705:Endocytosis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009893:Opossums; D059748:Proteolysis / Q000187:drug effects*; D011799:Quinazolines / Q000494:pharmacology; D012710:Serum Albumin, Bovine / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D019459:Urothelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: C576532:2-(2-(3,5-difluorophenyl)-acetylamino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo(e)(1,4)diazepin-3-yl)propionamide; D001570:Benzodiazepinones; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D005353:Fibronectins; D011799:Quinazolines; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D020032:Tyrphostins; C101044:RTKI cpd; D012710:Serum Albumin, Bovine; C512478:EGFR protein, human; D066246:ErbB Receptors; D053829:Amyloid Precursor Protein Secretases