Involvement of HB-EGF and EGF receptor transactivation in TGF-beta-mediated fibronectin expression in mesangial cells

Yoko Uchiyama-Tanaka, Hiroaki Matsubara, Yasukiyo Mori, Atsushi Kosaki, Noriko Kishimoto, Katsuya Amano, Shigeki Higashiyama, Toshiji Iwasaka
Kidney International 2002, 62 (3): 799-808

BACKGROUND: Gq-coupled receptors are known to transactivate epidermal growth factor receptor (EGFR) via the Ca2+ and PKC pathways to phosphorylate extracellular signal-regulated kinase (ERK).

METHODS: We studied the involvement of EGFR in transforming growth factor-beta (TGF-beta)-mediated fibronectin (FN) expression using glomerular mesangial cells.

RESULTS: TGF-beta up-regulated FN mRNA accumulation in a time- and dose-dependent manner, which was completely inhibited by phosphatidylcholine-phospholipase C (PC-PLC) inhibitor and PKC inhibitors (calphostin-C and staurosporin). The EGFR inhibitor AG1478 completely abolished TGF-beta-mediated FN expression. ERK inactivation by PD98059, and p38MAPK inhibitor SB203580 also showed significant inhibitory effects. Addition of neutralizing anti-heparin-binding EGF-like growth factor (HB-EGF) antibody, pretreatment with heparin and the metalloproteinase (MMP) inhibitor batimastat blocked FN expression. In mesangial cells stably transfected with a chimera containing HB-EGF and alkaline phosphatase (ALP) genes, ALP activity in incubation medium was rapidly increased by TGF-beta (2.1-fold at 0.5 min) and reached a 3.7-fold increase at two minutes, which was abolished by calphostin-C or batimastat. TGF-beta phosphorylated EGFR, ERK and p38MAPK in a PKC- and MMP-dependent manner. Smad2 phosphorylation by TGF-beta was not affected by AG1478, and HB-EGF did not activate Smad2. FN mRNA stability was not affected by TGF-beta. Cycloheximde did not interfere with TGF-beta-mediated FN expression.

CONCLUSIONS: The present study demonstrated that HB-EGF processed and released via PC-PLC-PKC signaling is an intermediate molecule for TGF-beta-mediated EGFR transactivation, and subsequent activation of ERK and p38MAPK is involved in FN expression via transcriptional regulation without requiring new protein synthesis.

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