Jpn. J. Pharmacol. 84 (2), 146-155 (2000)

Effect of Endothelin-1╩(1-31) on Human Mesangial Cell Proliferation

Masanori Yoshizumi1, Shoji Kagami2,, Yuki Suzaki1, Koichiro Tsuchiya1, Hitoshi Houchi1, Tetsuhiro Hisayama3, Hiroyuki Fukui3 and Toshiaki Tamaki1,*

Departments of 1Pharmacology and 2Pediatrics, The University of Tokushima School of Medicine, Tokushima 770-8503, Japan
3Department of Pharmacology, Faculty of Pharmaceutical Sciences, The University of Tokushima, Tokushima 770-8505, Japan
*Corresponding author.╩╩FAX:+81-88-633-7062

Abstract: It was previously found that human chymase cleaves big endothelins (ETs) at the Tyr31-Gly32 bond and produces 31-amino acid ETs╩(1-31). In the present study, human plasma concentrations of ET-1╩(1-31) and ET-1 were examined and the effect of synthetic ET-1╩(1-31) on the proliferation of cultured human mesangial cells (HMCs) was investigated. The proliferative effect of ET-1╩(1-31) was evaluated from the [3H]-thymidine uptake. The activity of extracellular signal-regulated kinase (ERK) and DNA binding activity of activator protein-1 were determined by using an in-gel kinase assay and gel mobility shift assay, respectively. Immunoreactive ET-1╩(1-31) was detectable in plasma, but the level was slightly lower than that of ET-1. ET-1╩(1-31) increased [3H]-thymidine incorporation in HMCs to a degree similar to that induced by ET-1. ET-1╩(1-31) also activated ERK1/2. Inhibition of protein kinase╩C and ERK kinase caused a reduction of ET-1╩(1-31)-induced ERK1/2 activation. The ERK1/2 activation was followed by an increase in transcription factor activator protein-1 DNA binding activity. These findings suggest that ET-1╩(1-31) is a bioactive peptide in humans and ET-1╩(1-31) itself stimulates HMC proliferation.

Keywords: Endothelin-1╩(1-31), Human chymase, Extracellular signal-regulated kinase, Protein kinase╩C

Copyrightę The Japanese Pharmacological Society 2000

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