<scp>MiR</scp> ‐21 suppression in macrophages promotes <scp>M2</scp> ‐like polarization and attenuates kidney ischemia–reperfusion injury
Xiaoyan Wang, Ting Ren, Xinni Zhang, Tianyi Pan, Fangyuan Peng, Jinghan Feng, Qian Sun, Nana Song, Xiaoqiang Ding, Ping Jia
Abstract
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.