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Depleting profibrotic macrophages using bioactivated in vivo assembly peptides ameliorates kidney fibrosis

Abstract

Managing renal fibrosis is challenging owing to the complex cell signaling redundancy in diseased kidneys. Renal fibrosis involves an immune response dominated by macrophages, which activates myofibroblasts in fibrotic niches. However, macrophages exhibit high heterogeneity, hindering their potential as therapeutic cell targets. Herein, we aimed to eliminate specific macrophage subsets that drive the profibrotic immune response in the kidney both temporally and spatially. We identified the major profibrotic macrophage subset (Fn1+Spp1+Arg1+) in the kidney and then constructed a 12-mer glycopeptide that was designated as bioactivated in vivo assembly PK (BIVA-PK) to deplete these cells. BIVA-PK specifically binds to and is internalized by profibrotic macrophages. By inducing macrophage cell death, BIVA-PK reshaped the renal microenvironment and suppressed profibrotic immune responses. The robust efficacy of BIVA-PK in ameliorating renal fibrosis and preserving kidney function highlights the value of targeting macrophage subsets as a potential therapy for patients with CKD.

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Data availability

All the data are available in the main text or the supplementary materials. The sc-RNA seq data that support the findings of this study are openly available in the Gene Expression Omnibus at https://www.ncbi.nlm.nih.gov/geo/, reference number GSE240885. All unique materials generated in this study, such as plasmids and cell lines, will be made available to researchers with a completed Materials Transfer Agreement upon request to the lead contact.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant numbers 82000657 to QO, 82030025, 32141005 to XC and E3041101 to LL) and the National Key R&D Program of China (grant number 2021YFC3002203 to LZ). We thank Dr. Jianwen Chen and Dr. Tiantian Wang for their help in establishing the uIRI mouse models. We thank Dr. Jiaqi Liu and Shaoyuan Cui for their help with confocal imaging.

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Contributions

QO and LL conceived and designed the study. QO and YT performed the scRNA-seq data analysis. LLL contributed to the synthesis of the glycol peptide. QO, CW, TS, YT, JZ, YC, and XW performed the in vitro and in vivo experiments. XW and RL established the mouse models and cultured the cells. PC and JL conducted the pathology analysis. WS performed the transmission electron microscopy analysis. QO, LW, ZF, XS, and LZ analyzed and interpreted the data. QO drafted the manuscript. LLL, GC, and XC supervised the study and edited the manuscript. All the authors have approved the submitted version of the manuscript.

Corresponding authors

Correspondence to Qing Ouyang, Guangyan Cai, Li-Li Li or Xiangmei Chen.

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Competing interests

QO, TS, LLL, and XC are co-inventors on China Invention Patent Application no. ZL 2022 1 0056384.3 filed by the Chinese PLA General Hospital related to the subject matter of this manuscript.

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Ouyang, Q., Wang, C., Sang, T. et al. Depleting profibrotic macrophages using bioactivated in vivo assembly peptides ameliorates kidney fibrosis. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01190-6

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