Guo Haixia, Liu Ziqian, Lv Ruyan, Zhang Boya, Qiang Panpan, Wang Xuan, Chang Yi, Yang Fan, Shimosawa Tatsuo, Xu Qingyou, Xiong Yunzhao
Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
Inflamm Res. 2025 May 24;74(1):85. doi: 10.1007/s00011-025-02044-1.
Inflammation plays a crucial role in the occurrence and development of renal fibrosis. Lymphatic vessels have emerged as new hotspots in the domain of inflammation. Recent studies have revealed that macrophages are involved in lymphangiogenesis through direct and indirect mechanisms. However, the underlying mechanisms of macrophage transdifferentiation into lymphatic endothelial cells (LECs) are still poorly understood.
In vivo, thirty male Wistar rats were randomly divided into a sham group, an aldosterone group and an aldosterone + esaxerenone group. In vitro, Raw 264.7 cells and bone marrow-derived macrophages (BMDMs) were used. H&E, Masson, western blotting, immunohistochemistry, immunofluorescence, flow cytometry, and BMDM tube formation assays were used to assess renal fibrosis and lymphangiogenesis in a rat model of aldosterone-induced renal injury.
In this study, we observed pathological renal fibrosis and lymphangiogenesis in 12-week-old rats after aldosterone infusion. In addition, the treatment of rats with esaxerenone, a mineralocorticoid receptor blocker (MRB), significantly reduced renal lymphangiogenesis and fibrosis. Interestingly, we found that aldosterone can activate MR to stimulate macrophages to secrete vascular endothelial growth factor C (VEGF-C) and promote lymphatic angiogenesis.
Our data suggest that renal fibrosis occurs in aldosterone-treated rats and that inflammation-induced macrophage transdifferentiation into LECs occurs during this process and that MRB attenuates renal fibrosis and lymphangiogenesis due to inflammatory injury.
炎症在肾纤维化的发生和发展中起关键作用。淋巴管已成为炎症领域的新热点。最近的研究表明，巨噬细胞通过直接和间接机制参与淋巴管生成。然而，巨噬细胞转分化为淋巴管内皮细胞（LEC）的潜在机制仍知之甚少。
在体内，将30只雄性Wistar大鼠随机分为假手术组、醛固酮组和醛固酮+依沙贝隆组。在体外，使用Raw 264.7细胞和骨髓来源的巨噬细胞（BMDM）。采用苏木精-伊红染色、Masson染色、蛋白质印迹法、免疫组织化学、免疫荧光、流式细胞术和BMDM管形成试验，评估醛固酮诱导的肾损伤大鼠模型中的肾纤维化和淋巴管生成。
在本研究中，我们观察到醛固酮输注后12周龄大鼠出现病理性肾纤维化和淋巴管生成。此外，用盐皮质激素受体阻滞剂（MRB）依沙贝隆治疗大鼠可显著减少肾淋巴管生成和纤维化。有趣的是，我们发现醛固酮可激活MR，刺激巨噬细胞分泌血管内皮生长因子C（VEGF-C）并促进淋巴管生成。
我们的数据表明，醛固酮治疗的大鼠会发生肾纤维化，在此过程中会发生炎症诱导的巨噬细胞转分化为LEC，并且MRB可减轻炎症损伤引起的肾纤维化和淋巴管生成。
