Mesenchymal stem cells alleviate acute kidney injury by down-regulating C5a/C5aR pathway activation
Acute kidney injury (AKI) leads to serious renal damage, and early inhibition of inflammation is necessary for its treatment. C5a/C5aR signaling activation promotes inflammatory response in tissue injury. Anti-inflammatory activity of mesenchymal stem cells (MSCs) makes it possible to alleviate AKI by controlling the C5a/C5aR signaling activation.
Ischemia reperfusion (I/R)-induced AKI models in wild-type and C5aR KO mice were used. In addition, human bone marrow MSCs (hBM-MSCs) or C5aR antagonist were injected in this model. All animals were killed at 72 h after reperfusion. In vitro, the LPS-activated macrophage line RAW264.7 cells were co-cultured with or without hBM-MSCs in the presence of recombinant C5a or not for indicated time points. After that, C5aR expression, the inflammatory factor production, and NF-κB translocation in RAW264.7 cells were measured.
hBM-MSC treatment and C5a/C5aR signaling blockade or C5aR-deficiency exhibited similar attenuated effects on I/R-induced AKI, macrophages infiltration, and the pro-inflammatory cytokines TNF-α and IL-1β expression in renal tissues in mice. Moreover, hBM-MSC administration led to a significant reduction in C5a levels in serum and C5aR expression in the kidney tissues in mice after I/R. In vitro, upon co-culture with hBM-MSCs, both C5aR expression and the secretion of pro-inflammatory factors TNF-α, IL-6, and nitric oxide in LPS-activated macrophages were markedly reduced. Accordingly, recombinant complement C5a accelerated LPS-induced NF-κB translocation and pro-inflammatory factors expression in macrophages, but the addition of hBM-MSCs reversed these C5a-induced effects.
The present study indicates that hBM-MSCs alleviate AKI via suppressing C5a/C5aR-NF-κB pathway activation.
KeywordsMSCs C5a/C5aR Macrophage AKI
This work was supported by National Natural Science Foundation of China (No. 81370846).
MT is acknowledged for study design, acquisition of data, statistical analysis, and drafting of the manuscript; KZ, YL, QZ, QH, and GL for technical and material support; KQZ for study design, analysis, and interpretation of data, writing, and revision of the article. All authors read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving animals were in accordance with the ethical standards of the Institutional Animal Care and Use Committee of the Third Military Medical University at which the studies were conducted.
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