C5a/C5aR pathway accelerates renal ischemia-reperfusion injury by downregulating PGRN expression.

Recent reports indicate that the complement C5a/C5aR pathway and progranulin (PGRN) deficiency both contribute to ischemia-reperfusion (IR)-induced acute kidney injury. However, the underlying relationship between the C5a/C5aR signaling pathway and PGRN expression during acute kidney injury is poorly understood. In this study, we showed that C5aR expression was significantly upregulated after renal IR, and that C5aR deficiency led to a marked increase in PGRN expression and a significant reduction in tubular damage and production of inflammatory cytokines. In accordance with these results, recombinant C5a caused downregulation of PGRN protein and mRNA levels in renal tubular epithelial cells (HK-2 cells), which could be negated by disruption of C5a/C5aR signaling by the C5aR antagonist, as confirmed by immunofluorescence, western blotting, and quantitative real-time PCR. Moreover, C5aR deficiency resulted in attenuated NF-κB expression 24h after IR, and recombinant C5a potentiated TNFα-induced NF-κB activation in HK-2 cells. Inhibition of NF-κB activation reversed C5a-induced downregulation of PGRN expression. Our results show for the first time that the complement C5a/C5aR pathway aggravates IR-induced acute kidney injury by suppressing PGRN expression and confirm that suppression of PGRN expression is associated with increased NF-κB activation induced by C5a.

Zhang K ，Li GQ ，He QH ，Li Y ，Tang M ，Zheng QY ，Xu GL ，Zhang KQ ... -  《-》

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

Tang M ，Zhang K ，Li Y ，He QH ，Li GQ ，Zheng QY ，Zhang KQ ... -  《-》

C5a/C5aR pathway is essential for up-regulating SphK1 expression through p38-MAPK activation in acute liver failure.

Lei YC ，Lu CL ，Chen L ，Ge K ，Yang LL ，Li W ，Wu YH ... -  《-》

Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils.

de Vries B ，Köhl J ，Leclercq WK ，Wolfs TG ，van Bijnen AA ，Heeringa P ，Buurman WA ... -  《-》

Complement C5a-C5aR interaction enhances MAPK signaling pathway activities to mediate renal injury in trichloroethylene sensitized BALB/c mice.

We have previously shown complement activation as a possible mechanism for trichloroethylene (TCE) sensitization, leading to multi-organ damage including the kidneys. In particular, excessive deposition of C5 and C5b-9-the membrane attack complex, which can generate significant tissue damage, was observed in the kidney tissue after TCE sensitization. The present study tested the hypothesis that anaphylatoxin C5a binding to its receptor C5aR mediates renal injury in TCE-sensitized BALB/c mice. BALB/c mice were sensitized through skin challenge with TCE, with or without pretreatment by the C5aR antagonist W54011. Kidney histopathology and the renal functional test were performed to assess renal injury, and immunohistochemistry and fluorescent labeling were carried out to assess C5a and C5aR expressions. TCE sensitization up-regulated C5a and C5aR expressions in kidney tissue, generated inflammatory infiltration, renal tubule damage, glomerular hypercellularity and impaired renal function. Antagonist pretreatment blocked C5a binding to C5aR and attenuated TCE-induced tissue damage and renal dysfunction. TCE sensitization also caused the deposition of major pro-inflammatory cytokines IL-2, TNF-α and IFN-γ in the kidney tissue (P < 0.05); this was accompanied by increased expression of P-p38, P-ERK and P-JNK proteins (P < 0.05). Pretreatment with the C5aR antagonist attenuated the increase of expression of P-p38, P-ERK and P-JNK proteins (P < 0.05) and also consistently reduced the TCE sensitization-induced increase of IL-2, TNF-α and IFN-γ (P < 0.05). These data identify C5a binding to C5aR, MAP kinase activation, and inflammatory cytokine release as a novel mechanism for complement-mediated renal injury by sensitization with TCE or other environmental chemicals.

Zhang JX ，Zha WS ，Ye LP ，Wang F ，Wang H ，Shen T ，Wu CH ，Zhu QX ... -  《-》