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Updated: Jun 5, 2025
Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration
Published on: June 7, 2014
MiR-21 suppression in macrophages promotes M2-like polarization and attenuates kidney ischemia-reperfusion injury
Xiaoyan Wang1, Ting Ren1, Xinni Zhang1
1Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China.
Abstract:
MicroRNA-21 (miR-21) is one of the most frequently upregulated miRNAs in response to kidney ischemia-reperfusion (IR) injury, exhibiting both protective and pathogenic effects depending on the cell type, disease state, and target signaling. In this study, we analyzed the function of miR-21 in various cell types to elucidate its role in ischemia-induced inflammation and acute kidney injury (AKI). Utilizing a mouse model of IR injury, we observed significant upregulation of miR-21 in renal tubular epithelial cells and macrophages following IR. Deletion of miR-21 in macrophages mitigated IR-induced pro-inflammatory cytokine production and AKI. However, conditional deletion of miR-21 in proximal tubules or nonproximal tubules did not protect the kidneys against these effects. Mechanistically, miR-21 inhibition promoted M2-like polarization in macrophages and suppressed M1-like polarization and proinflammatory cytokine production in kidneys. In vitro, miR-21 knockdown in the mouse macrophage cell line Raw246.7 or genetic deletion of miR-21 in bone marrow-derived macrophages (BMDMs) increased the percentage of CD206+ cells (M2 phenotype) while decreasing the percentage of CD86+ cells (M1 phenotype) and the expressions of proinflammatory cytokines. Overexpression of miR-21 in Raw264.7 cells reduced the percentage of CD206+ cells. Furthermore, we demonstrated that signal transducer and activator of transcription 3 (STAT3) was a target gene of miR-21 in macrophages, and miR-21 deletion promoted M2 macrophage polarization via STAT3 activation. In conclusion, miR-21 plays a role in regulating macrophage polarization, and the blockade of miR-21/STAT3 signaling may represent a novel therapeutic strategy for the prevention or treatment of AKI.
Insights
MicroRNA-21 (miR-21) in macrophages, not kidney cells, drives inflammation and acute kidney injury (AKI) after ischemia-reperfusion. Blocking miR-21/STAT3 signaling may treat AKI.
Area of Science:
- Nephrology
- Molecular Biology
- Immunology
Background:
- MicroRNA-21 (miR-21) is upregulated in kidney ischemia-reperfusion (IR) injury.
- miR-21 has complex roles, potentially protective or pathogenic, depending on context.
- Its specific function in IR-induced inflammation and acute kidney injury (AKI) requires elucidation.
Purpose of the Study:
- To investigate the role of miR-21 in various kidney cell types during IR injury.
- To determine the impact of miR-21 on ischemia-induced inflammation and AKI.
- To elucidate the underlying molecular mechanisms involving macrophage polarization.
Main Methods:
- Utilized a mouse model of kidney IR injury.
- Analyzed miR-21 expression in renal tubular epithelial cells and macrophages.
- Investigated the effects of miR-21 deletion in specific cell types (macrophages, proximal tubules, nonproximal tubules).
- Performed in vitro studies using macrophage cell lines (Raw264.7) and bone marrow-derived macrophages (BMDMs).
- Assessed macrophage polarization (M1/M2 markers) and cytokine production.
- Identified signal transducer and activator of transcription 3 (STAT3) as a miR-21 target.
Main Results:
- miR-21 was significantly upregulated in macrophages and renal tubular cells post-IR.
- Macrophage-specific deletion of miR-21 mitigated IR-induced inflammation and AKI.
- Deletion in tubular cells did not confer protection.
- miR-21 inhibition promoted M2 macrophage polarization and suppressed M1 polarization and pro-inflammatory cytokine production.
- miR-21 knockdown/deletion in macrophages increased M2 markers (CD206+) and decreased M1 markers (CD86+).
- miR-21 targeted STAT3 in macrophages, with miR-21 deletion promoting M2 polarization via STAT3 activation.
Conclusions:
- miR-21 critically regulates macrophage polarization during kidney IR injury.
- Macrophage miR-21, not tubular miR-21, contributes to AKI pathogenesis.
- Targeting the miR-21/STAT3 signaling pathway in macrophages offers a potential therapeutic strategy for AKI.
