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.
- Autosomal recessive polycystic kidney disease
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