TY - JOUR
T1 - 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
AU - Boehn, Susanne N.E.
AU - Spahn, Sonja
AU - Neudecker, Sabine
AU - Keppler, Andrea
AU - Bihoreau, Marie Thérèse
AU - Kränzlin, Bettina
AU - Pandey, Priyanka
AU - Hoffmann, Sigrid C.
AU - Li, Li
AU - Torres, Vicente E.
AU - Gröne, Hermann Josef
AU - Gretz, Norbert
N1 - Funding Information:
We thank Elisabeth Wühl, Viktoria Skude, Mareike Gill, and other colleagues for excellent technical support. This work was supported by the DFG Research Training Group 886 ‘Molecular Imaging methods for the analysis of gene and protein expression’.
PY - 2013/8
Y1 - 2013/8
N2 - 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.
AB - 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.
KW - Catechol-O-methyltransferase
KW - Gene expression profiling
KW - Modifier
KW - Polycystic kidney disease
KW - Tolcapone
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U2 - 10.1093/ndt/gft014
DO - 10.1093/ndt/gft014
M3 - Article
C2 - 23543593
AN - SCOPUS:84884576860
VL - 28
SP - 2045
EP - 2058
JO - Proceedings of the European Dialysis and Transplant Association - European Renal Association. European Dialysis and Transplant Association - European Renal Association. Congress
JF - Proceedings of the European Dialysis and Transplant Association - European Renal Association. European Dialysis and Transplant Association - European Renal Association. Congress
SN - 0931-0509
IS - 8
ER -