title: Inhibition of Comt with tolcapone slows progression of polycystic kidney disease in the more severely affected PKD/Mhm (cy/+) substrain of the Hannover Sprague-Dawley rat.
abstract: BACKGROUND
  Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human inherited diseases. Modifier genes seem to modulate the disease progression and might therefore be promising drug targets. Although a number of modifier loci have been already identified, no modifier gene has been proven to be a real modifier yet.
  
  
  METHODS
  Gene expression profiling of two substrains of the Han:SPRD rat, namely PKD/Mhm and PKD/US, both harboring the same mutation, was conducted in 36-day-old animals. Catechol-O-methyltransferase (Comt) was identified as a potential modifier gene. A 3-month treatment with tolcapone, a selective inhibitor of Comt, was carried out in PKD/Mhm and PKD/US (cy/+) animals.
  
  
  RESULTS
  Comt is localized within a known modifier locus of PKD (MOP2). The enzyme encoding gene was found upregulated in the more severely affected PKD/Mhm substrain and was hence presumed to be a putative modifier gene of PKD. The treatment with tolcapone markedly attenuated the loss of renal function, inhibited renal enlargement, shifted the size distribution of renal cysts and retarded cell proliferation, apoptosis, inflammation and fibrosis development in affected (cy/+) male and female PKD/Mhm and PKD/US rats.
  
  
  CONCLUSIONS
  Comt has been confirmed to be the first reported modifier gene for PKD and tolcapone offers a promising drug for treating PKD.
authors.affiliation: Medical Research Center, University of Heidelberg, Mannheim, Germany.
authors.forename: Susanne N E
authors.initials: SN
authors.lastname: Boehn
authors.forename: Sonja
authors.initials: S
authors.lastname: Spahn
authors.forename: Sabine
authors.initials: S
authors.lastname: Neudecker
authors.forename: Andrea
authors.initials: A
authors.lastname: Keppler
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Bihoreau
authors.forename: Bettina
authors.initials: B
authors.lastname: Kränzlin
authors.forename: Priyanka
authors.initials: P
authors.lastname: Pandey
authors.forename: Sigrid C
authors.initials: SC
authors.lastname: Hoffmann
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001577:Benzophenones / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D065098:Catechol O-Methyltransferase Inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D009596:Nitrophenols / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D007690:Polycystic Kidney Diseases / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077867:Tolcapone
chemical_list: D001577:Benzophenones; D015415:Biomarkers; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D012333:RNA, Messenger; D000077867:Tolcapone
keywords: catechol-O-methyltransferase; gene expression profiling; modifier; polycystic kidney disease; tolcapone
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