The Effect of cAMP-PKA Activation on TGF-beta 1-Induced Profibrotic Signaling

Background: The cAMP-PKA signaling pathway and TGF-beta 1-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 kidnay-cyst model to study the regulat ory role of cAMP-PKA signaling in the TGF-beta 1 induced fibrotic process.Method and 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 thefibrosis-related proteins TGF-beta 11, FN and collagen type I were highly expressed. Western blotting revealed the obviously up-regulation of TGF-beta 1, CTGF, FN and collagen typed I expression following forskolin treatment in MDCK cells. Selective PKA inhibition with H89 may partially reversed the above effects. Pretreatment with the TGF-beta 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-beta-induced ERK1/2 phosphorylation and FN p-regulation. ERK inhibition useing PD98059 significantly inhibited the expression of CTGF,FN and collagen type I causd by TGF-beta 1. Conclusion: The cAMP-PKA signaling pathway can directly promote the production of TGF-beta 1 and/or TGF-beta 1 and its downstream pathways were highly ecpressed MDCK cells, cAMP-PKA had a significantly negative effect on TGF-beta induced p-ERK1/2 and FN expression. Copyright (C) 2015 S. Karger AG, Basel