title: Suppression of PAI-1 expression through inhibition of the EGFR-mediated signaling cascade in rat kidney fibroblast by ascofuranone.
abstract: Fibrosis in glomerulosclerosis causes progressive loss of renal function. Transforming growth factor (TGF)-beta, one of the major profibrotic cytokines, induces the synthesis of plasminogen activator inhibitor (PAI)-1, a factor that plays a crucial role in the development of fibrosis. Here, we found that an isoprenoid antibiotic, ascofuranone, suppresses expression of profibrotic factors including matrix proteins and PAI-1 induced by TGF-beta in renal fibroblasts. Ascofuranone selectively inhibits phosphorylation of epidermal growth factor receptor (EGFR), and downstream kinases such as Raf-1, MEK-1/2, and ERK-1/2. PAI-1 transcription also is suppressed by treatment with kinase inhibitors for MEK-1/2 or EGFR, and with small interfering RNA for EGFR. Ascofuranone inhibits cellular metalloproteinase activity, and an inhibitor of metalloproteinases suppresses EGFR phosphorylation and PAI-1 transcription. These results suggest that ascofuranone suppresses expression of profibrotic factors through the inhibition of an EGFR-dependent signal transduction pathway activated by metalloproteinases.
authors.affiliation: Department of Medicine, Catholic University of Daegu School of Medicine, Korea.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Cho
authors.forename: Jeong-Han
authors.initials: JH
authors.lastname: Kang
authors.forename: Teoan
authors.initials: T
authors.lastname: Kim
authors.forename: Kwang-Kyun
authors.initials: KK
authors.lastname: Park
authors.forename: Cheorl-Ho
authors.initials: CH
authors.lastname: Kim
authors.forename: In-Seon
authors.initials: IS
authors.lastname: Lee
authors.forename: Kwan-Sik
authors.initials: KS
authors.lastname: Min
authors.forename: Junji
authors.initials: J
authors.lastname: Magae
authors.forename: Hiroo
authors.initials: H
authors.lastname: Nakajima
authors.forename: Young-Seuk
authors.initials: YS
authors.lastname: Bae
authors.forename: Young-Chae
authors.initials: YC
authors.lastname: Chang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015153:Blotting, Western; D066246:ErbB Receptors / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013729:Terpenes / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D017395:Plasminogen Activator Inhibitor 1; D047428:Protein Kinase Inhibitors; D012717:Sesquiterpenes; D013729:Terpenes; D066246:ErbB Receptors; C006640:ascofuranone