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

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.