| First Author | Weng L | Year | 2015 |
| Journal | Cell Physiol Biochem | Volume | 36 |
| Issue | 5 | Pages | 1911-27 |
| PubMed ID | 26202352 | Mgi Jnum | J:319179 |
| Mgi Id | MGI:6863029 | Doi | 10.1159/000430160 |
| Citation | Weng L, et al. (2015) The Effect of cAMP-PKA Activation on TGF-beta1-Induced Profibrotic Signaling. Cell Physiol Biochem 36(5):1911-27 |
| abstractText | BACKGROUND: The cAMP-PKA signaling pathway and TGF-beta1-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-beta1 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 the fibrosis-related proteins TGF-beta1, 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-beta1, FN and collagen type I were highly expressed. Western blotting revealed the obviously up-regulation of TGF-beta1, 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-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 up-regulation. ERK inhibition useing PD98059 significantly inhibited the expression of CTGF, FN and collagen type I caused by TGF-beta1. CONCLUSIONS: The cAMP-PKA signaling pathway can directly promote the production of TGF-beta1 and/or TGF-beta1-dependent fibrogenetic molecules in MDCK cells and embryonic kidney cysts, but when TGF-beta1 and its downstream pathways were highly expressed in MDCK cells, cAMP-PKA had a significantly negative effect on TGF-beta1 induced p-ERK1/2 and FN expression. |
