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Chondroitin sulfate mediates liver responses to injury induced by dual endothelin receptor inhibition.

Canadian journal of physiology and pharmacology (2020-04-22)
Gusty Rizky Teguh Ryanto, Kennosuke Yorifuji, Koji Ikeda, Noriaki Emoto
ABSTRACT

Although dual endothelin receptor antagonists (ERAs) show great promise for treating various conditions, their propensity to induce liver injury limits their clinical usage. Inflammation and fibrosis are important processes in liver responses to injury and it has been suggested that they and dual ERA-induced liver injury are mediated by the proteoglycan component chondroitin sulfate (CS), which is synthesized by CHST3 and CHST13. In this study, we investigated whether dual ER inhibition in the liver could alter CHST3 and CHST13 expression and thus CS production and whether liver CS content could prevent inflammatory and fibrosis responses after liver injury. We observed increased CHST3 and CHST13 expression after liver injury in bile duct ligated mice and histologically confirmed abundant CS deposition in the injured liver. Moreover, treating Hep3B cells with a dual ERA mimic significantly increased CHST3 and CHST13 expression, inflammatory cytokine levels, and glycosaminoglycan deposition. Furthermore, pro-inflammatory and pro-fibrotic markers were observed after dual ERA treatment, while treatment with CS-degrading chondroitinase ABC was able to successfully reverse these phenotypes. These observations suggest that CHST3- and CHST13-induced CS production can mediate liver injury responses caused by dual ER inhibition and thus could be an alternative pathway for treating ERA-induced liver injury.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Lipopolysaccharides from Escherichia coli O111:B4, γ-irradiated, BioXtra, suitable for cell culture
Sigma-Aldrich
Chondroitinase ABC from Proteus vulgaris, BSA free, lyophilized powder, specific activity 50-250 units/mg protein
Sigma-Aldrich
Anti-Actin, α-Smooth Muscle - FITC antibody, Mouse monoclonal antibody produced in mouse, clone 1A4, purified from hybridoma cell culture
Sigma-Aldrich
BQ-123, ≥99%, sodium salt, lyophilized powder
Sigma-Aldrich
Solketal methacrylate, 50 wt. % in dichloromethane, contains ~280 ppm 4-tert-butylcatechol as inhibitor
Sigma-Aldrich
BQ-788, ≥95%, solid