Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
Int J Urol. 2024 Jun;31(6):685-692. doi: 10.1111/iju.15427. Epub 2024 Feb 17.
Erythropoietin (EPO) exerts tissue-protective effects on various organs including the kidney. However, the effects of EPO on established renal fibrosis remain unclear. In this study, we aimed to examine the therapeutic potential of EPO against established renal fibrosis.
Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) and the mice were treated with recombinant human EPO (rhEPO) daily during 7 and 13 days after UUO. The degrees of renal fibrosis, myofibroblast accumulation, and macrophage infiltration; the mRNA expression levels of transforming growth factor (TGF)-β1 and α1(I) collagen; and the protein levels of Kelch-like ECH-associated protein 1 (Keap1) and nuclear NF-E2-related factor 2 (Nrf2) in the kidneys were assessed on day 14 after UUO.
Treatment with rhEPO significantly decreased fibrosis, myofibroblast accumulation, and α1(I) collagen mRNA expression, but it did not significantly affect TGF-β1 mRNA expression. Although treatment with rhEPO did not significantly affect the total number of interstitial macrophages, it significantly decreased the number of CD86-positive cells (M1 macrophages), while significantly increased the number of CD206-positive cells (M2 macrophages) in the interstitium. Treatment with rhEPO did not affect the Keap1/Nrf2 protein level or the peripheral blood hematocrit value.
These results indicate for the first time that EPO exerts antifibrotic effects against the evolution of established renal fibrosis, possibly by influencing the polarization of infiltrating macrophages.
促红细胞生成素(EPO)对包括肾脏在内的各种器官具有组织保护作用。然而,EPO 对已建立的肾纤维化的影响尚不清楚。在本研究中,我们旨在研究 EPO 对已建立的肾纤维化的治疗潜力。
通过单侧输尿管梗阻(UUO)在小鼠中诱导肾纤维化,在 UUO 后 7 和 13 天期间每天用重组人 EPO(rhEPO)治疗小鼠。在 UUO 后 14 天评估肾脏纤维化、肌成纤维细胞积累和巨噬细胞浸润的程度、转化生长因子(TGF)-β1 和α1(I)胶原的 mRNA 表达水平以及肾脏中的 Kelch 样 ECH 相关蛋白 1(Keap1)和核 NF-E2 相关因子 2(Nrf2)的蛋白水平。
rhEPO 治疗显著降低了纤维化、肌成纤维细胞积累和α1(I)胶原 mRNA 表达,但对 TGF-β1 mRNA 表达没有显著影响。虽然 rhEPO 治疗并没有显著影响间质中总巨噬细胞的数量,但它显著减少了 CD86 阳性细胞(M1 巨噬细胞)的数量,同时显著增加了 CD206 阳性细胞(M2 巨噬细胞)的数量。rhEPO 治疗不影响 Keap1/Nrf2 蛋白水平或外周血红细胞压积值。
这些结果首次表明,EPO 对已建立的肾纤维化的进展具有抗纤维化作用,可能通过影响浸润巨噬细胞的极化来实现。