TY - JOUR
T1 - Activation of the AKTmTOR pathway in autosomal recessive polycystic kidney disease (ARPKD)
AU - Fischer, Dagmar Christiane
AU - Jacoby, Ulrike
AU - Pape, Lars
AU - Ward, Christopher J.
AU - Kuwertz-Broeking, Eberhard
AU - Renken, Catharina
AU - Nizze, Horst
AU - Querfeld, Uwe
AU - Rudolph, Birgit
AU - Mueller-Wiefel, Dirk E.
AU - Bergmann, Carsten
AU - Haffner, Dieter
N1 - Funding Information:
Acknowledgements. The study was supported by a research grant of the Else Kröner-Fresenius Stiftung, Bad Homburg, Germany (P60/07) and the Deutsche Forschungsgemeinschaft (DFG). Thanks are due to Dr V. Bröcker (Department of Pathology, Hannover Medical School, Germany) for providing archival tissues. The authors wish to thank Anja Rahn, Birgit Salewski and Birgit Jasper for outstanding technical assistance.
PY - 2009/6
Y1 - 2009/6
N2 - Background. Autosomal recessive polycystic kidney disease (ARPKD) MIM 263200 belongs to a group of congenital hepatorenal fibrocystic syndromes and is caused by mutations in the PKHD1 gene encoding the multidomain protein fibrocystinpolyductin (FPC). The serine-threonine kinase mammalian target of rapamycin (mTOR) is one of the most important gate-keepers integrating numerous signals related to cell proliferation and growth. Whereas the direct activation of mTOR has been shown recently in autosomal-dominant PKD, no data are available on the role of mTOR signalling in proliferation and progression of ARPKD.Methods. Formalin-fixed and paraffin-embedded kidney specimens obtained during nephrectomy from children with ARPKD (n = 12) were used for immunohistochemical investigation of FPC expression (monoclonal antibody (mAb) 18, mAb 5a), proliferative activity (Ki-67) and activation of the mTOR pathway. Kidney specimens from children (n = 4) who died from causes not associated with kidney disease served as controls. For the detection of AKT, mTOR and S6K antibodies specifically recognizing the activated (phosphorylated) isoforms of these proteins were used. In all patients mutation analysis of the PKHD1 gene was performed.Results. In 10 out of 12 patients, we could confirm the diagnosis by the identification of PKHD1 mutations. The tubular cyst epithelium of all kidney specimens stained strongly positive with the FPC-specific monoclonal antibody (mAb) 18 but only very faint signals were obtained with mAb 5a. In contrast, healthy kidneys showed rather weak signals with both FPC-specific mAbs, indicating dysregulated expression of FPC in our patients. Phosphorylated AKT as well as activated mTOR and its down-stream effector S6K were strongly expressed in cystic epithelia of all kidney specimens but not in control tissues. No association between the activation of this pathway and the proliferative activity (Ki-67 expression) was observed.Conclusions. Our results point to a central role of AKTmTOR signalling in ARPKD and justify further investigations to evaluate the therapeutic potential of mTOR inhibitors in ARPKD patients.
AB - Background. Autosomal recessive polycystic kidney disease (ARPKD) MIM 263200 belongs to a group of congenital hepatorenal fibrocystic syndromes and is caused by mutations in the PKHD1 gene encoding the multidomain protein fibrocystinpolyductin (FPC). The serine-threonine kinase mammalian target of rapamycin (mTOR) is one of the most important gate-keepers integrating numerous signals related to cell proliferation and growth. Whereas the direct activation of mTOR has been shown recently in autosomal-dominant PKD, no data are available on the role of mTOR signalling in proliferation and progression of ARPKD.Methods. Formalin-fixed and paraffin-embedded kidney specimens obtained during nephrectomy from children with ARPKD (n = 12) were used for immunohistochemical investigation of FPC expression (monoclonal antibody (mAb) 18, mAb 5a), proliferative activity (Ki-67) and activation of the mTOR pathway. Kidney specimens from children (n = 4) who died from causes not associated with kidney disease served as controls. For the detection of AKT, mTOR and S6K antibodies specifically recognizing the activated (phosphorylated) isoforms of these proteins were used. In all patients mutation analysis of the PKHD1 gene was performed.Results. In 10 out of 12 patients, we could confirm the diagnosis by the identification of PKHD1 mutations. The tubular cyst epithelium of all kidney specimens stained strongly positive with the FPC-specific monoclonal antibody (mAb) 18 but only very faint signals were obtained with mAb 5a. In contrast, healthy kidneys showed rather weak signals with both FPC-specific mAbs, indicating dysregulated expression of FPC in our patients. Phosphorylated AKT as well as activated mTOR and its down-stream effector S6K were strongly expressed in cystic epithelia of all kidney specimens but not in control tissues. No association between the activation of this pathway and the proliferative activity (Ki-67 expression) was observed.Conclusions. Our results point to a central role of AKTmTOR signalling in ARPKD and justify further investigations to evaluate the therapeutic potential of mTOR inhibitors in ARPKD patients.
KW - AKT-signalling
KW - Autosomal recessive polycystic kidney disease
KW - Fibrocystinpolyduction
KW - Immunohistochemistry
KW - MTOR-pathway
UR - http://www.scopus.com/inward/record.url?scp=67651100822&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67651100822&partnerID=8YFLogxK
U2 - 10.1093/ndt/gfn744
DO - 10.1093/ndt/gfn744
M3 - Article
C2 - 19176689
AN - SCOPUS:67651100822
SN - 0931-0509
VL - 24
SP - 1819
EP - 1827
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - 6
ER -