Suppression of PAI-1 expression through inhibition of the EGFR-mediated signaling cascade in rat kidney fibroblast by ascofuranone.
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.
Cho
Hyun-Ji
HJ
Department of Medicine, Catholic University of Daegu School of Medicine, Korea.
Kang
Jeong-Han
JH
Kim
Teoan
T
Park
Kwang-Kyun
KK
Kim
Cheorl-Ho
CH
Lee
In-Seon
IS
Min
Kwan-Sik
KS
Magae
Junji
J
Nakajima
Hiroo
H
Bae
Young-Seuk
YS
Chang
Young-Chae
YC
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
D000900:Anti-Bacterial Agents; D017395:Plasminogen Activator Inhibitor 1; D047428:Protein Kinase Inhibitors; D012717:Sesquiterpenes; D013729:Terpenes; D066246:ErbB Receptors; C006640:ascofuranone