title: Elevated TGFbeta-Smad signalling in experimental Pkd1 models and human patients with polycystic kidney disease.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited renal disease characterized by many fluid-filled cysts and interstitial fibrosis in the kidneys, leading to chronic renal failure. During cystogenesis the renal tubules undergo extensive structural alterations that are accompanied by altered cellular signalling, directly and/or indirectly regulated by the PKD1 and PKD2 proteins. Since transforming growth factor (TGF)-beta signalling modulates cell proliferation, differentiation, apoptosis, adhesion and migration of various cell types, we studied the activation of this signalling pathway in Pkd1-mutant mouse models at different stages of the disease. Therefore, we analysed expression of the TGFbeta-Smad signalling pathway and its target genes in different Pkd1 mutant mouse models in various stages of polycystic disease. Nuclear accumulation of P-Smad2 in cyst lining epithelial cells was not observed in the initiation phase but was observed at mild and more advanced stages of PKD. This coincides with mild fibrosis and increased mRNA levels of TGFbeta target genes, such as fibronectin, collagen type I, plasminogen activator inhibitor 1 and matrix metalloproteinase-2. At this stage many interstitial fibroblasts were found around cysts, which also showed nuclear localization for P-Smad2. However, bone morphogenetic protein (BMP) signalling, which can antagonize TGFbeta signalling, is not affected, since nuclear expression of P-Smad1/5/8 and expression of the BMP target gene, inhibitor of DNA binding/differential-1 (ID-1) is not altered compared to wild-type controls. Also, human kidneys with progressive ADPKD showed increased nuclear localization of P-Smad2, while in general expression of P-Smad1/5/8 was weak. These results exclude TGFbeta signalling at the initiation of cystogenesis, but indicate an important role during cyst progression and in fibrogenesis of progressive ADPKD.
authors.affiliation: Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Sabrine
authors.initials: S
authors.lastname: Hassane
authors.forename: Wouter N
authors.initials: WN
authors.lastname: Leonhard
authors.forename: Annemieke
authors.initials: A
authors.lastname: van der Wal
authors.forename: Lukas Jac
authors.initials: LJ
authors.lastname: Hawinkels
authors.forename: Irma S
authors.initials: IS
authors.lastname: Lantinga-van Leeuwen
authors.forename: Peter
authors.initials: P
authors.lastname: ten Dijke
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Breuning
authors.forename: Emile
authors.initials: E
authors.lastname: de Heer
authors.forename: Dorien Jm
authors.initials: DJ
authors.lastname: Peters
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D007690:Polycystic Kidney Diseases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000235:genetics / Q000502:physiology*; D050396:TRPP Cation Channels / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D051785:Smad Proteins; D050396:TRPP Cation Channels; D016212:Transforming Growth Factor beta