MicroRNA-382 Promotes M2-Like Macrophage via the SIRP-α/STAT3 Signaling Pathway in Aristolochic Acid-Induced Renal Fibrosis.

Abstract

Aristolochic acid nephropathy (AAN) is a type of drug-induced nephropathy and is correlated with a potentially progression of kidney fibrosis. However, whether miR-382 is implicated in macrophage activation in AA-induced kidney fibrosis remains elusive. Here, cell-sorting experiments defined a significant miR-382 enrichment in renal macrophage after AAN 14 days. Then, we found that treatment of AA induced a significant switch in the phenotype of macrophage both in vivo and in vitro. Furthermore, miR-382 knockout (KO) mice and miR-382-/- bone marrow-derived macrophage (BMDM) were subjected to AA induction. We found that both systemic KO and macrophage-specific miR-382 depletion notably suppressed M2-like macrophage activation as well as kidney interstitial fibrosis. Additionally, adoptive transfer of miR-382 overexpression BMDMs into mice promoted AA-induced kidney injury. Moreover, in cultured macrophage, upregulation of miR-382 promoted M2-related gene expression, accompanied by downregulation of signal regulatory protein α (SIRP-α) and activation of signal transducer and activator of transcription 3 (STAT3). The interaction between miR-382 and SIRP-α was evaluated via dual-luciferase assay. Knockdown of SIRP-α upregulated phosphorylated STAT3 at S727 and Y705. Pharmacological inhibition of STAT3 was performed both in vivo and in vitro. Inhibition of STAT3 attenuated AA-induced kidney fibrosis, in parallel to lesser macrophage M2 polarization. Coculture experiments further confirmed that overexpressed miR-382 in macrophage promoted injuries of tubular cells. Luminex bio-chip detection suggested that IL-4 and CCL-5 were critical in the cross talk between macrophages and tubular cells. Taken together, our data suggest that miR-382 is a critical mediator in M2-like macrophage polarization and can be a promising therapeutic target for kidney fibrosis.

• Authors: Xiaoyan Wang, Ping Jia, Ting Ren, Zhouping Zou, Sujuan Xu, Yunlu Zhang, Yiqin Shi, Siyu Bao, Yingxiang Li, Yi Fang, Xiaoqiang Ding
• Journal: Frontiers in immunology (Front Immunol) Vol. 13 Pg. 864984 ( 2022) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 35585990 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Wang, Jia, Ren, Zou, Xu, Zhang, Shi, Bao, Li, Fang and Ding.

Chemical References

• Aristolochic Acids
• MicroRNAs
• Ptpns1 protein, mouse
• Receptors, Immunologic
• STAT3 Transcription Factor
• Stat3 protein, mouse
• microRNA 382, mouse
• aristolochic acid I

Topics

• Animals
• Aristolochic Acids
• Fibrosis
• Kidney Diseases (chemically induced, metabolism)
• Macrophage Activation
• Macrophages (metabolism)
• Mice
• Mice, Knockout
• MicroRNAs (genetics, metabolism)
• Receptors, Immunologic
• STAT3 Transcription Factor (metabolism)
• Signal Transduction