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Int Urol Nephrol. 2018 Aug;50(8):1545-1553. doi: 10.1007/s11255-018-1844-7. Epub 2018 Mar 28.

Mesenchymal stem cells alleviate acute kidney injury by down-regulating C5a/C5aR pathway activation.

Author information

1
Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
2
Department of Immunology, Third Military Medical University, Chongqing, 400038, China.
3
Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China. zhkq@tmmu.edu.cn.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

The present study indicates that hBM-MSCs alleviate AKI via suppressing C5a/C5aR-NF-κB pathway activation.

KEYWORDS:

AKI; C5a/C5aR; MSCs; Macrophage

PMID:
29594894
DOI:
10.1007/s11255-018-1844-7
[Indexed for MEDLINE]

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