2. Academic Validation
  3. Trametinib alleviates lipopolysaccharide-induced acute kidney injury by inhibiting macrophage polarization through the PI3K/Akt pathway

Trametinib alleviates lipopolysaccharide-induced acute kidney injury by inhibiting macrophage polarization through the PI3K/Akt pathway

  • Transpl Immunol. 2025 Jan 30:89:102183. doi: 10.1016/j.trim.2025.102183.
Yingqi Zeng 1,  Wenjia Yuan 1,  Chen Feng 1,  Longkai Peng 1,  Xubiao Xie 1,  Fenghua Peng 1,  Tengfang Li 1,  Minjie Lin 2,  Hedong Zhang 3,  Helong Dai 4
Affiliations

Affiliations

  • 1 Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China.
  • 2 Academic Affairs Department, The Second Xiangya Hospital of Central South University, Changsha 410011, China.
  • 3 Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China. Electronic address: 269610769@qq.com.
  • 4 Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China; Clinical Research Center for Organ Transplantation in Hunan Province, Central South University, Changsha, China. Electronic address: helong68888@csu.edu.cn.
PMID: 39892762 DOI: 10.1016/j.trim.2025.102183
Abstract

Background: Sepsis-induced acute kidney injury (AKI) is a severe condition characterized by dysregulation of pro- and anti-inflammatory responses. Targeting macrophage polarization between pro-inflammatory M1 and anti-inflammatory M2 cells offers a potential therapeutic approach for AKI. Trametinib (TRAM), an inhibitor of the MEK1/2 signaling pathway, was evaluated for its impact on M1/M2 polarization in AKI.

Methods: Wild-type (WT) mice were subjected to lipopolysaccharide (LPS)-induced AKI and intraperitoneally treated with dimethyl sulfoxide (DMSO) or TRAM (10 mg/kg) for three days. Renal function was assessed by measuring creatinine levels. While histopathological changes, RNA Sequencing data, and serum cytokine levels were analyzed. Macrophage M1/M2 polarization in kidney tissues was examined using flow cytometry and immunohistochemistry. Murine bone marrow-derived macrophages (BMDMs) were polarized to the M1 or M2 phenotype in vivo and treated with or without TRAM (10 μM). M1/M2 polarization was analyzed via flow cytometry, and PI3K/Akt signaling was evaluated by western blotting.

Results: TRAM significantly improved renal function, as demonstrated by reduced serum creatinine levels (p < 0.01) and ameliorated histopathological damage (p < 0.01). Flow cytometry and immunohistochemistry revealed that TRAM markedly inhibited pro-inflammatory M1 macrophage polarization (p < 0.001). Additionally, TRAM reduced serum level of IFN-γ (p < 0.01) and IL-17 (p < 0.001). In vitro, TRAM suppressed M1 polarization (p < 0.05) by inhibiting the PI3K/Akt signaling pathway.

Conclusion: TRAM mitigated LPS-induced AKI by suppressing M1 macrophage polarization via the PI3K/Akt pathway, highlighting its therapeutic potential for AKI and Other inflammatory kidney diseases.

Keywords

Acute kidney injury; Inflammation; Macrophage polarization; Trametinib.

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