Suppression of PAI-1 expression through inhibition of the EGFR-mediated signaling cascade in rat kidney fibroblast by ascofuranone

✍ Scribed by Hyun-Ji Cho; Jeong-Han Kang; Teoan Kim; Kwang-Kyun Park; Cheorl-Ho Kim; In-Seon Lee; Kwan-Sik Min; Junji Magae; Hiroo Nakajima; Young-Seuk Bae; Young-Chae Chang

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 278 KB
• Volume: 107
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.22130

✦ Synopsis

Abstract

Fibrosis in glomerulosclerosis causes progressive loss of renal function. Transforming growth factor (TGF)‐β, 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‐β 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. J. Cell. Biochem. 107: 335–344, 2009. © 2009 Wiley‐Liss, Inc.