Division of Infection Control, Department of Nephrology and Laboratory Medicine, Kanazawa University, 13-1 Takara-machi, 920-8641, Kanazawa , Japan.
Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan.
BMC Nephrol. 2021 May 31;22(1):203. doi: 10.1186/s12882-021-02411-0.
The number of patients with end stage kidney disease (ESKD) are increasing world-side. While interstitial fibrosis (IF) is a common step for the progression to ESKD, therapeutic options for IF is still limited in clinical settings. We have reported that bone marrow-derived fibrotic cell, fibrocyte, is involved in the pathogenesis of kidney fibrosis. Also recent studies revealed that erythropoietin has protective effect on kidney diseases. However, it is unknown whether erythropoietin (EPO) inhibits fibrosis in progressive kidney injury. Therefore, we explored the impacts of EPO on kidney fibrosis with focusing on fibrocyte.
Fibrocyte was differentiated from peripheral mononuclear cells of healthy donor. Fibrocyte was stimulated with transforming growth factor beta (TGF)-β with/without EPO treatment. Moreover, the therapeutic effect of EPO was evaluated in murine unilateral ureteral obstruction (UUO) model.
TGF-β stimulation increased the expression of COL1 mRNA in fibrocyte. EPO signal reduced the expression of COL1 mRNA in dose dependent manner. EPO reduced mitochondrial oxidative stress and ameliorated mitochondrial membrane depolarization induced by TGF-β stimulation. Moreover, EPO reduced the mRNA expression of mitochondria related molecules, TRAF6, in fibrocyte. In addition, the count of CD45+/αSMA + double-positive fibrocyte was decreased in the EPO-administered UUO kidneys.
EPO signals function to prevent kidney fibrosis, particularly in fibrocyte. Regulating the renal accumulation of fibrocyte is a part of the anti-fibrotic functions of EPO.
世界各地终末期肾病（ESKD）患者的数量正在增加。虽然间质纤维化（IF）是进展为 ESKD 的常见步骤，但在临床环境中，IF 的治疗选择仍然有限。我们已经报告说，骨髓来源的纤维化细胞，纤维母细胞，参与了肾脏纤维化的发病机制。最近的研究还表明，促红细胞生成素对肾脏疾病有保护作用。然而，促红细胞生成素（EPO）是否抑制进行性肾损伤中的纤维化尚不清楚。因此，我们通过关注纤维母细胞来探讨 EPO 对肾脏纤维化的影响。
纤维母细胞从健康供体的外周单核细胞中分化而来。用转化生长因子β（TGF）-β刺激纤维母细胞，有/无 EPO 处理。此外，还在单侧输尿管梗阻（UUO）模型中评估了 EPO 的治疗效果。
TGF-β刺激增加了纤维母细胞中 COL1 mRNA 的表达。EPO 信号以剂量依赖的方式降低 COL1 mRNA 的表达。EPO 减轻了 TGF-β刺激引起的线粒体氧化应激和膜去极化。此外，EPO 降低了纤维母细胞中线粒体相关分子 TRAF6 的 mRNA 表达。此外，EPO 给药的 UUO 肾脏中 CD45+/αSMA+双阳性纤维母细胞计数减少。
EPO 信号可预防肾脏纤维化，特别是在纤维母细胞中。调节肾脏中纤维母细胞的积累是 EPO 抗纤维化功能的一部分。
