title: The Effect of cAMP-PKA Activation on TGF-β1-Induced Profibrotic Signaling.
abstract: BACKGROUND
  The cAMP-PKA signaling pathway and TGF-β1-dependent fibrosis pathways are of particular importance in ADPKD progression, but the cross-talk between these pathways remains unclear. Therefore, we used an MDCK-cell model and embryonic kidney-cyst model to study the regulatory role of cAMP-PKA signaling in the TGF-β1 induced fibrotic process.
  
  
  RESULTS
  Pkd1(flox/flox); Ksp-Cre and Pkd1(+/+); Ksp-Cre mice were used as an in vivo model. Increased kidney volume, renal cysts formation and up-regulation of the fibrosis-related proteins TGF-β1, connective tissue growth factor (CTGF), and fibronectin (FN) can be observed in Pkd1(flox/flox); Ksp-Cre mice. In an embryonic kidneys-cyst model, TGF-β1, FN and collagen type I were highly expressed. Western blotting revealed the obviously up-regulation of TGF-β1, CTGF, FN and collagen type I expression following forskolin treatment in MDCK cells. Selective PKA inhibition with H89 may partially reversed the above effects. Pretreatment with the TGF-β RI kinase inhibitor VI SB431542 suppressed the increased expression of CTGF, FN and collagen type I caused by forskolin. Our data also indicate that forskolin inhibited TGF-β-induced ERK1/2 phosphorylation and FN up-regulation. ERK inhibition useing PD98059 significantly inhibited the expression of CTGF, FN and collagen type I caused by TGF-β1.
  
  
  CONCLUSIONS
  The cAMP-PKA signaling pathway can directly promote the production of TGF-β1 and/or TGF-β1-dependent fibrogenetic molecules in MDCK cells and embryonic kidney cysts, but when TGF-β1 and its downstream pathways were highly expressed in MDCK cells, cAMP-PKA had a significantly negative effect on TGF-β1 induced p-ERK1/2 and FN expression.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Peking University, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, PR. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Weng
authors.forename: Weiling
authors.initials: W
authors.lastname: Wang
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Su
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Limin
authors.initials: L
authors.lastname: Su
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
authors.forename: Baoxue
authors.initials: B
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004285:Dogs; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005355:Fibrosis / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D017868:Cyclic AMP-Dependent Protein Kinases