title: A novel inhibitor of tumor necrosis factor-alpha converting enzyme ameliorates polycystic kidney disease.
abstract: BACKGROUND
  Transforming growth factor-alpha (TGF-alpha) expression is abnormal in polycystic kidney disease. We previously demonstrated that blockade of the epidermal growth factor receptor (EGFR), the receptor for TGF-alpha, significantly slowed disease progression in the bpk murine model of autosomal-recessive kidney disease (ARPKD). In the present study, kidney TGF-alpha expression in this model is characterized, and the therapeutic potential of inhibiting TGF-alpha in ARPKD is examined using a novel inhibitor of tumor necrosis factor-alpha converting enzyme (TACE), the metalloproteinase that cleaves membrane-bound TGF-alpha to release the secreted ligand.
  
  
  METHODS
  Immunohistochemistry (IH) and Western analysis were performed on kidneys from cystic bpk mice and noncystic littermates at postnatal days 7, 14, and 21. Bpk mice and normal controls were treated with WTACE2, a competitive inhibitor of TACE, from day 7 until day 21, and the effects on kidney histology and renal function were assessed.
  
  
  RESULTS
  Increased TGF-alpha expression by IH was demonstrated in the proximal tubules (PT) at postnatal day 7 and collecting tubules (CT) by day 21. A parallel increase in kidney TGF-alpha expression was demonstrated by Western analysis. Treatment of cystic bpk mice with WTACE2 resulted in a 43% reduction in kidney weight to body weight ratio (11.2 vs. 19.7%), improved cystic index (3.2 vs. 4.8), reduced cystic CT to PT ratio (1.2 vs. 8), and a greater than 30% reduction in BUN and serum creatinine.
  
  
  CONCLUSIONS
  These findings support the pathophysiological role of the TGF-alpha/EGFR axis in murine ARPKD and demonstrate that inhibition of TGF-alpha secretion has therapeutic potential in PKD.
authors.affiliation: Rainbow Center for Childhood PKD, Department of Pediatrics, Rainbow Babies and Children's Hospital and Case Western Reserve University Cleveland, Ohio 44106-6003, USA. kmd8@po.cwru.edu
authors.forename: K M
authors.initials: KM
authors.lastname: Dell
authors.forename: R
authors.initials: R
authors.lastname: Nemo
authors.forename: W E
authors.initials: WE
authors.lastname: Sweeney
authors.forename: J I
authors.initials: JI
authors.lastname: Levin
authors.forename: P
authors.initials: P
authors.lastname: Frost
authors.forename: E D
authors.initials: ED
authors.lastname: Avner
mesh_terms: D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development / Q000378:metabolism; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008815:Mice, Inbred Strains; D017044:Polycystic Kidney, Autosomal Recessive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000627:therapeutic use*; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: D006877:Hydroxamic Acids; D013449:Sulfonamides; D016211:Transforming Growth Factor alpha; C442468:WTACE2 compound; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse