Interplay between Endothelin and Erythropoietin in Astroglia: The Role in Protection against Hypoxia

Richard Schäfer,Matthias Schwab,Christoph Gleiter,Reinhild Buecheler,Lars Mueller,Lusine Danielyan,Barbara Proksch

doi:10.3390/ijms15022858

Abstract

We show that, under in vitro conditions, the vulnerability of astroglia to hypoxia is reflected by alterations in endothelin (ET)-1 release and capacity of erythropoietin (EPO) to regulate ET-1 levels. Exposure of cells to 24 h hypoxia did not induce changes in ET-1 release, while 48–72 h hypoxia resulted in increase of ET-1 release from astrocytes that could be abolished by EPO. The endothelin receptor type A (ETA) antagonist BQ123 increased extracellular levels of ET-1 in human fetal astroglial cell line (SV-FHAS). The survival and proliferation of rat primary astrocytes, neural precursors, and neurons upon hypoxic conditions were increased upon administration of BQ123. Hypoxic injury and aging affected the interaction between the EPO and ET systems. Under hypoxia EPO decreased ET-1 release from astrocytes, while ETA receptor blockade enhanced the expression of EPO mRNA and EPO receptor in culture-aged rat astroglia. The blockade of ETA receptor can increase the availability of ET-1 to the ETB receptor and can potentiate the neuroprotective effects of EPO. Thus, the new therapeutic use of combined administration of EPO and ETA receptor antagonists during hypoxia-associated neurodegenerative disorders of the central nervous system (CNS) can be suggested.

Highlights

Endothelin (ET), a potent vasoconstrictor peptide (MW: 2.492 kDa), was isolated for the first time in 1988 from porcine endothelial cells (ECs) [1]
Treatment of DIV7 astrocytes with BQ123 under normoxic conditions did not reveal significant changes in EPO mRNA expression compared to untreated normoxic controls (Figure 1A, N vs. N + BQ123)
Treatment of DIV21 astrocytes with BQ123 under normoxic conditions did not reveal any changes in EPO mRNA expression compared to untreated normoxic controls (Figure 1B, N vs. N + BQ123)

Summary

Introduction

Endothelin (ET), a potent vasoconstrictor peptide (MW: 2.492 kDa), was isolated for the first time in 1988 from porcine endothelial cells (ECs) [1]. ET-1 was shown to be expressed in ECs and in tissues such as liver, lung, kidney, and brain [2,3]. The expression of the ET gene is increased by adrenalin, vasopressin, angiotensin II, growth factors, and cytokines, whereas nitric oxide, natriuretic peptide and heparin decrease the ET gene expression [4]. ETA and ETB receptors feature different binding affinities for ET isoforms and differ from each other by their amino acid sequences. The ETA receptor is known as a high affinity receptor for ET-1 whereas the ETB receptor shows an equal affinity for all ET isoforms [5]. The ETA receptor mediates the classical vasoconstricting action via G protein activation, whereas the ETB receptor comes in two subtypes: activation of ETB1 receptor results in vasodilatation while ETB2 receptor mediates vasoconstriction [6,7]

Results

Discussion

Conclusion