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Kidney Week

Abstract: PO0371

A Novel Immunomodulatory Peptide Suppresses Inflammatory Macrophages and Mitigates AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Chu, Chih-Wei, University of California Davis, Davis, California, United States
  • Yang, David, University of California Davis, Davis, California, United States
  • Hsu, Ssu-Wei, University of California Davis, Davis, California, United States
  • Chen, Ching-Hsien, University of California Davis, Davis, California, United States
Background

Monocytes/macrophages are known to play a critical role in the pathogenesis and progression of acute kidney injury (AKI), as large numbers of monocytes are recruited to the kidney and differentiate into pro-inflammatory macrophages (M1 phenotype) after injury. Although targeting macrophages has emerged as a promising therapeutic strategy for AKI, the effective treatment is still limited. We previously identified a novel peptide, the MPS peptide, which targets the signaling molecule myristoylated alanine-rich C-kinase substrate (MARCKS), a central inducer of M1 macrophages. In this study, we have employed this novel peptide to determine if MARCKS inhibition reduces kidney injury.

Methods

High-dimensional single-cell mass spectrometry was used to reveal immune profiling in an AKI mouse model. Both commercial macrophage cell lines and primary macrophages isolated from peripheral blood mononuclear cells were utilized in this study for gene expression analysis. In vitro and in vivo inflammatory activities of the MPS peptide were confirmed by Western blots, real-time reverse transcription-polymerase chain reaction (RT-qPCR), flow cytometry, ELISA cytokine assays, and immunohistochemistry.

Results

Analysis of the single-cell RNA sequencing data has identified that the immune microenvironment of injured kidneys is associated with the expansion of monocytes/macrophages, particularly M1 macrophages. We next show that an elevated abundance of phospho-MARCKS in macrophages upon cisplatin treatment and this increase occurred in parallel with an increase of M1 markers as well as upregulation of inflammatory cytokines and markers of nephrotoxicity in cisplatin-exposed kidneys. Mechanistically, we demonstrate that MPS peptide had an inhibitory effect on cisplatin-induced phospho-MARCKS, p65 phosphorylation, and NF-κB activation in macrophages. Targeting of MARCKS phosphorylation using MPS peptide not only downregulated kidney-infiltrating M1 macrophages but also suppressed levels of serum creatinine and blood urea nitrogen in mice exposed to cisplatin.

Conclusion

Our results suggest that MARCKS phosphorylation is a novel NF-kB activator in pro-inflammatory macrophages and also presents a proof of concept for the use of MPS peptide as a renal protection agent for AKI.

Funding

  • Other U.S. Government Support