Chondroitin sulfate mediates liver responses to injury induced by dual endothelin receptor inhibition
Chondroitin sulfate mediates liver responses to injury induced by dual endothelin receptor inhibition
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DOI：
10.1139/cjpp-2019-0649
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发表时间：
2020-09-01
影响因子：
2.1
通讯作者：
Emoto, Noriaki
中科院分区：
文献类型：
--
作者：
Ryanto, Gusty Rizky Teguh;Yorifuji, Kennosuke;Emoto, Noriaki
尽管双重内皮素受体拮抗剂（ERA）在治疗各种疾病方面显示出巨大的前景，但其诱导肝损伤的倾向限制了其临床应用。炎症和纤维化是肝脏对损伤的反应中的重要过程，并且已经表明它们和双重ERA诱导的肝损伤是由蛋白聚糖组分硫酸软骨素（CS）介导的，其由CHST 3和CHST 13合成。在这项研究中，我们研究了肝脏中的双重ER抑制是否可以改变CHST3和CHST13的表达，从而改变CS的产生，以及肝脏CS含量是否可以预防肝损伤后的炎症和纤维化反应。我们观察到胆管结扎小鼠肝损伤后CHST 3和CHST 13表达增加，组织学证实损伤肝脏中有大量CS沉积。此外，用双重ERA模拟物处理Hep3B细胞显著增加CHST 3和CHST 13表达、炎性细胞因子水平和糖胺聚糖沉积。此外，在双重ERA治疗后观察到促炎和促纤维化标志物，而用CS降解软骨素酶ABC治疗能够成功逆转这些表型。这些观察结果表明，CHST 3和CHST 13诱导的CS产生可以介导由双重ER抑制引起的肝损伤反应，因此可能是治疗ERA诱导的肝损伤的替代途径。
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. Weobserved 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.