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  3. Aldosterone induces renal lymphangiogenesis through macrophage-lymphatic endothelial cell transformation and Inhibition by esaxerenone

Aldosterone induces renal lymphangiogenesis through macrophage-lymphatic endothelial cell transformation and Inhibition by esaxerenone

  • Inflamm Res. 2025 May 24;74(1):85. doi: 10.1007/s00011-025-02044-1.
Haixia Guo # 1 2,  Ziqian Liu # 1 2,  Ruyan Lv # 1 2,  Boya Zhang 1 2,  Panpan Qiang 2 3,  Xuan Wang 1 2 3,  Yi Chang 2 3,  Fan Yang 2 3,  Tatsuo Shimosawa 4,  Qingyou Xu 5 6 7 8,  Yunzhao Xiong 9 10 11 12
Affiliations

Affiliations

  • 1 Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
  • 2 Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
  • 3 Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China.
  • 4 Department of Clinical Laboratory, School of Medicine, International University of Health and Welfare, Narita, 286-8686, Japan.
  • 5 Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China. qingyouxu@hebcm.edu.cn.
  • 6 Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China. qingyouxu@hebcm.edu.cn.
  • 7 Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China. qingyouxu@hebcm.edu.cn.
  • 8 Department of Internal Medicine, Hebei University of Chinese Medicine, 326 Xinshinan Road, Shijiazhuang, 050091, China. qingyouxu@hebcm.edu.cn.
  • 9 Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China. xiongyunzhao616@hebcm.edu.cn.
  • 10 Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China. xiongyunzhao616@hebcm.edu.cn.
  • 11 Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, China. xiongyunzhao616@hebcm.edu.cn.
  • 12 Department of Internal Medicine, Hebei University of Chinese Medicine, 326 Xinshinan Road, Shijiazhuang, 050091, China. xiongyunzhao616@hebcm.edu.cn.
  • # Contributed equally.
PMID: 40413281 DOI: 10.1007/s00011-025-02044-1
Abstract

Objective and design: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

Aldosterone; Lymphangiogenesis; Macrophages; Mineralocorticoid receptor; Mineralocorticoid receptor blocker; VEGF-C.

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