A synthetic retinoic acid receptor agonist Am80 ameliorates renal fibrosis via inducing the production of alpha-1-acid glycoprotein
A synthetic retinoic acid receptor agonist Am80 ameliorates renal fibrosis via inducing the production of alpha-1-acid glycoprotein
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DOI：
10.1038/s41598-020-68337-z
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发表时间：
2020-07-10
影响因子：
4.6
通讯作者：
Maruyama，Toru
中科院分区：
文献类型：
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作者：
Watanabe，Hiroshi;Bi，Jing;Maruyama，Toru
肾脏纤维化是慢性肾脏疾病进展的主要因素，也是肾脏损伤的最终共同途径。因此，迫切需要针对肾纤维化的有效治疗方法。本研究的目的是观察合成维甲酸受体激动剂AM80对单侧输尿管梗阻(UUO)小鼠肾间质纤维化的治疗作用。结果表明，AM80治疗对肾脏纤维化和炎症的抑制程度与自然产生的维甲酸-全反式维甲酸(AtRA)相同。但与全反式维甲酸治疗相比，AM80治疗的小鼠体重减轻的不良影响较小。给健康小鼠服用AM80后，RAR激动剂下游分子α-1-酸性糖蛋白(AGP)的mRNA水平升高。此外，在经Am80处理的HepG2细胞和THP-1来源的巨噬细胞中，也观察到AGP mRNA的表达增加。AGP基因敲除小鼠加重了UUO小鼠的肾纤维化、炎症反应和巨噬细胞的浸润，提示内源性AGP在肾纤维化的形成过程中起到了抗纤维化和抗炎的作用。我们还发现，在UUO处理的AGP基因敲除小鼠中，Am80没有观察到抗纤维化作用，而atRA处理倾向于显示部分抗纤维化作用。这些共同的发现表明，AM80通过参与AGP功能来预防肾脏纤维化。
Renal fibrosis is a major factor in the progression of chronic kidney disease and the final common pathway of kidney injury. Therefore, the effective therapies against renal fibrosis are urgently needed. The objective of this study was to investigate the effect of Am80, a synthetic retinoic acid receptor (RAR) agonist, in the treatment of renal interstitial fibrosis using unilateral ureteral obstruction (UUO) mice. The findings indicate that Am80 treatment suppressed renal fibrosis and inflammation to the same degree as the naturally-occuring retinoic acid, all-trans retinoic acid (atRA). But the adverse effect of body weight loss in Am80-treated mice was lower compared to the atRA treatment. The hepatic mRNA levels of alpha-1-acid glycoprotein (AGP), a downstream molecule of RAR agonist, was increased following administration of Am80 to healthy mice. In addition, increased AGP mRNA expression was also observed in HepG2 cells and THP-1-derived macrophages that had been treated with Am80. AGP-knockout mice exacerbated renal fibrosis, inflammation and macrophage infiltration in UUO mice, indicating endogenous AGP played an anti-fibrotic and anti-inflammatory role during the development of renal fibrosis. We also found that no anti-fibrotic effect of Am80 was observed in UUO-treated AGP-knockout mice whereas atRA treatment tended to show a partial anti-fibrotic effect. These collective findings suggest that Am80 protects against renal fibrosis via being involved in AGP function.