BackgroundIncreasing evidence demonstrates a phenotypic plasticity of endothelial cells (ECs). Endothelial-to-mesenchymal transition (EndMT) contributes to the development of tissue fibrosis. However, the pathogenic factors and signalling pathways regulating this process in ischaemia/reperfusion (I/R) injury are still poorly understood.MethodsWe investigated the possible role of complement in the induction of this endothelial dysfunction in a swine model of renal I/R injury by using recombinant C1 inhibitor in vivo.ResultsHere, we showed that I/R injury reduced the density of renal peritubular capillaries and induced tissue fibrosis with generation of CD31+/α-SMA + and CD31+/FPS-1+ cells indicating EndMT. When we inhibited complement, the process of EndMT became rare, with preserved density of peritubular capillaries and significant reduction in renal fibrosis. When we activated ECs by anaphylatoxins in vitro, C3a and C5a led to altered endothelial phenotype with increased expression of fibroblast markers and decrease expression of specific endothelial markers. The activation of Akt pathway was pivotal for the C3a and C5a-induced EndMT in vitro. In accordance, inhibition of complement in vivo led to the abrogation of Akt signalling, with hampered EndMT and tissue fibrosis.ConclusionsOur data demonstrate a critical role for complement in the acute induction of EndMT via the Akt pathway. Therapeutic inhibition of these systems may be essential to prevent vascular damage and tissue fibrosis in transplanted kidney. © The Author 2014.

Curci, C., Castellano, G., Stasi, A., Divella, C., Loverre, A., Gigante, M., Simone, S., Cariello, M., Montinaro, V., Lucarelli, G., Ditonno, P., Battaglia, M., Crovace, A., Staffieri, F., Oortwijn, B., Van Amersfoort, E., Gesualdo, L., Grandaliano, G., Endothelial-to-mesenchymal transition and renal fibrosis in ischaemia/reperfusion injury are mediated by complement anaphylatoxins and Akt pathway, <<NEPHROLOGY DIALYSIS TRANSPLANTATION>>, 2014; 29 (4): 799-808. [doi:10.1093/ndt/gft516] [http://hdl.handle.net/10807/196981]

Endothelial-to-mesenchymal transition and renal fibrosis in ischaemia/reperfusion injury are mediated by complement anaphylatoxins and Akt pathway

Grandaliano, G.
2014

Abstract

BackgroundIncreasing evidence demonstrates a phenotypic plasticity of endothelial cells (ECs). Endothelial-to-mesenchymal transition (EndMT) contributes to the development of tissue fibrosis. However, the pathogenic factors and signalling pathways regulating this process in ischaemia/reperfusion (I/R) injury are still poorly understood.MethodsWe investigated the possible role of complement in the induction of this endothelial dysfunction in a swine model of renal I/R injury by using recombinant C1 inhibitor in vivo.ResultsHere, we showed that I/R injury reduced the density of renal peritubular capillaries and induced tissue fibrosis with generation of CD31+/α-SMA + and CD31+/FPS-1+ cells indicating EndMT. When we inhibited complement, the process of EndMT became rare, with preserved density of peritubular capillaries and significant reduction in renal fibrosis. When we activated ECs by anaphylatoxins in vitro, C3a and C5a led to altered endothelial phenotype with increased expression of fibroblast markers and decrease expression of specific endothelial markers. The activation of Akt pathway was pivotal for the C3a and C5a-induced EndMT in vitro. In accordance, inhibition of complement in vivo led to the abrogation of Akt signalling, with hampered EndMT and tissue fibrosis.ConclusionsOur data demonstrate a critical role for complement in the acute induction of EndMT via the Akt pathway. Therapeutic inhibition of these systems may be essential to prevent vascular damage and tissue fibrosis in transplanted kidney. © The Author 2014.
2014
Inglese
Curci, C., Castellano, G., Stasi, A., Divella, C., Loverre, A., Gigante, M., Simone, S., Cariello, M., Montinaro, V., Lucarelli, G., Ditonno, P., Battaglia, M., Crovace, A., Staffieri, F., Oortwijn, B., Van Amersfoort, E., Gesualdo, L., Grandaliano, G., Endothelial-to-mesenchymal transition and renal fibrosis in ischaemia/reperfusion injury are mediated by complement anaphylatoxins and Akt pathway, <<NEPHROLOGY DIALYSIS TRANSPLANTATION>>, 2014; 29 (4): 799-808. [doi:10.1093/ndt/gft516] [http://hdl.handle.net/10807/196981]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/196981
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