2. Academic Validation
  3. Esaxerenone inhibits renal macrophage proliferation through MR/TGF-β1 pathway in db/db mice

Esaxerenone inhibits renal macrophage proliferation through MR/TGF-β1 pathway in db/db mice

  • Life Sci. 2025 Oct 9:382:124008. doi: 10.1016/j.lfs.2025.124008.
Fengwen Yang 1,  Ziqian Liu 2,  Yuan Li 1,  Ruyan Lv 2,  Yicong Zhao 1,  Fan Yang 3,  Tatsuo Shimosawa 4,  Jinchuan Tan 1,  Qingyou Xu 5,  Panpan Qiang 6
Affiliations

Affiliations

  • 1 Hebei University of Chinese Medicine, Shijiazhuang, 050200, China; The First Affiliated Hospital of Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
  • 2 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.
  • 3 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; Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.
  • 4 Department of Clinical Laboratory, School of Medicine, International University of Health and Welfare, Narita, 286-8686, Japan.
  • 5 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; Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China. Electronic address: qingyouxu@hebcm.edu.cn.
  • 6 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; Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China. Electronic address: qiangpanpan@hebcm.edu.cn.
PMID: 41067301 DOI: 10.1016/j.lfs.2025.124008
Abstract

Aims: To investigate the effect of Mineralocorticoid Receptor (MR) blockade esaxerenone on renal macrophage proliferation in db/db mice and its potential role in the progression of diabetic kidney disease (DKD).

Materials and methods: Eight-week-old db/db mice were administered esaxerenone at a dose of 1 mg/kg/day for six weeks. The origin of macrophages (resident versus recruited) and their phenotypic subtypes (M1 vs. M2) were evaluated using molecular markers, including F4/80, Ki-67, Ly6C, iNOS, and CD206. Immunohistochemistry, flow cytometry, and single-cell RNA Sequencing were utilized to evaluate these parameters. The inhibitory effects of esaxerenone and the TGF-β1 inhibitor LY2109761 on the proliferation of bone marrow-derived macrophages (BMDMs) under high-glucose conditions were examined in vitro.

Key findings: Marked increases in macrophage infiltration and proliferation were observed in the kidneys of db/db mice. Both recruited and resident macrophages exhibited significant proliferative activity, with recruited macrophages predominantly adopting an M1 phenotype and resident macrophages primarily exhibiting an M2 phenotype. Proliferating macrophages displayed enhanced pro-inflammatory and pro-fibrotic responses compared to non-proliferating counterparts. In vivo, esaxerenone treatment significantly suppressed macrophage proliferation. In vitro studies demonstrated that high glucose activated MR, upregulated TGF-β1 expression, and subsequently promoted BMDMs proliferation, particularly within the M1 subtype. TGF-β1 alone also induced BMDMs proliferation, an effect attenuated by LY2109761.

Significance: Esaxerenone inhibits renal macrophage proliferation mediated by high glucose-induced activation of MR and downstream TGF-β1 signaling pathways, thereby mitigating inflammatory and fibrotic damage. These findings suggest that MR blockade may directly target macrophage proliferation and inflammation in DKD.

Keywords

Diabetic kidney disease; High glucose; Macrophage; Mineralocorticoid receptor; Proliferation.

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